Novel benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake

ABSTRACT

Provided are novel benzothiepines, derivatives, and analogs thereof; pharmaceutical compositions containing them; and methods of using these compounds and compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as those associated with atherosclerosis or hypercholesterolemia, in mammals.

[0001] This application is a continuation-in-part application of U.S.application Ser. No. 09/816,065, filed Mar. 11, 1997, which claims thebenefit of priority of U.S. Provisional Application Serial No.60/013,119, filed Mar. 11, 1996. This application is also acontinuation-in-part application of U.S. application Ser. No.09/831,284, filed Mar. 31, 1997, which is a continuation of U.S.application Ser. No. 08/517,051, filed Aug. 21, 1995, which is acontinuation-in-part application of U.S. application Ser. No.08/305,526, filed Sep. 12, 1994. This is application also claimspriority from U.S. Provisional Application Serial No. 60/068,170 filedDec. 19, 1997.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to novel benzothiepines,derivatives and analogs thereof, pharmaceutical compositions containingthem, and their use in medicine, particularly in the prophylaxis andtreatment of hyperlipidemic conditions such as is associated withatherosclerosis or hypercholesterolemia, in mammals.

[0004] 2. Description of Related Art

[0005] It is well-settled that hyperlipidemic conditions associated withelevated concentrations of total cholesterol and low-density lipoproteincholesterol are major. risk factors for coronary heart disease andparticularly atherosclerosis. Interfering with the circulation of bileacids within the lumen of the intestinal tract is found to reduce thelevels of serum cholesterol in a causal relationship. Epidemiologicaldata has accumulated which indicates such reduction leads to animprovement in the disease state of atherosclerosis. Stedronsky, in“Interaction of bile acids and cholesterol with nonsystemic agentshaving hypocholesterolemic properties,” Biochimica et Biophysica Acta,1210 (1994) 255-287 discusses the biochemistry, physiology and knownactive agents surrounding bile acids and cholesterol.

[0006] Pathophysiologic alterations are shown to be consistent withinterruption of the enterohepatic circulation of bile acids in humans byHeubi, J. E., et al. See “Primary Bile Acid Malabsorption: Defective inVitro Ileal Active Bile Acid Transport”, Gastroenterology,1982:83:804-11.

[0007] In fact, cholestyramine binds the bile acids in the intestinaltract, thereby interfering with their normal enterohepatic circulation(Reihner, E. et al, in “Regulation of hepatic cholesterol metabolism inhumans: stimulatory effects of cholestyramine on HMG-CoA reductaseactivity and low density lipoprotein receptor expression in gallstonepatients”, Journal of Lipid Research, Volume 31, 1990, 2219-2226 andSuckling el al, “Cholesterol Lowering and bile acid excretion in thehamster with cholestyramine treatment”, Atherosclerosis, 89(1991)183-190). This results in an increase in liver bile acid synthesis bythe liver using cholesterol as well as an upregulation of the liver LDLreceptors which enhances clearance of cholesterol and decreases serumLDL cholesterol levels.

[0008] In another approach to the reduction of recirculation of bileacids, the ileal bile acid transport system is a putative pharmaceuticaltarget for the treatment of hypercholesterolemia based on aninterruption of the enterohepatic circulation with specific transportinhibitors (Kramer, et al, “Intestinal Bile Acid Absorption” The Journalof Biological Chemistry, Vol. 268, No. 24, Issue of Aug. 25, pp.18035-18046, 1993).

[0009] In a series of patent applications, eg Canadian PatentApplication Nos. 2,025,294; 2,078,588; 2,085,782; and 2,085,830; and EPApplication Nos. 0 379 161; 0 549 967; 0 559 064; and 0 563 731, HoechstAktiengesellschaft discloses polymers of various naturally occurringconstituents of the enterohepatic circulation system and theirderivatives, including bile acid, which inhibit the physiological bileacid transport with the goal of reducing the LDL cholesterol levelsufficiently to be effective as pharmaceuticals and, in particular foruse as hypocholesterolemic agents.

[0010] In vitro bile acid transportinhibition is disclosed to showhypolipidemic activity in The Wellcome Foundation Limited disclosure ofthe world patent application number WO 93/16055 for “HypolipidemicBenzothiazepine Compounds” Selected benzothiepines are disclosed inworld patent application number WO93/321146 for numerous uses includingfatty acid metabolism and coronary vascular diseases.

[0011] Other selected benzothiepines are known for use as hypolipaemicand hypocholesterolaemic agents, especially for the treatment orprevention of atherosclerosis as disclosed by application Nos. EP508425, FR 2661676, and WO 92/18462, each of which is limited by anamide bonded to the carbon adjacent the phenyl ring of the fused bicyclobenzothiepine ring.

[0012] The above references show continuing efforts to find safe,effective agents for the prophylaxis and treatment of hyperlipidemicdiseases and their usefulness as hypocholesterolemic agents.

[0013] Additionally selected benzothiepines are disclosed for use invarious disease states not within the present invention utility. Theseare EP 568 898A as abstracted by Derwent Abstract No. 93-351589; WO89/1477/A as abstracted in Derwent Abstract No. 89-370688; U.S. Pat. No.3,520,891 abstracted in Derwent 50701R-B; U.S. Pat. No. 3,287,370, U.S.Pat. No. 3,389,144; U.S. Pat. No. 3,694,446 abstracted in Derwent Abstr.No. 65860T-B and WO 92/18462.

[0014] The present invention furthers such efforts by providing novelbenzothiepines, pharmaceutical compositions, and methods of usetherefor.

SUMMARY OF THE INVENTION

[0015] Accordingly, among its various apects, the present inventionprovides compounds of formula (I):

[0016] wherein:

[0017] q is an integer from 1 to 4;

[0018] n is an integer from 0 to 2;

[0019] R¹ and R² are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy,alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl,

[0020] wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl,alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, andcycloalkyl optionally are substituted with one or more substituentsselected from the group consisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R²A⁻, SR⁹,S⁺R⁹R¹⁰A⁻. P⁺R⁹R¹⁰R¹¹A⁻, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo,and CONR⁹R¹⁰,

[0021] wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl,(polyalkyl)aryl, and cycloalkyl optionally have one or more carbonsreplaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻, P⁺R⁹R¹⁰A⁻, orphenylene,

[0022] wherein R⁹, R¹⁰, and R^(w) are independently selected from thegroup consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl,carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino,heteroarylalkyl, heterocyclylalkyl, and alkylammoniumalkyl; or

[0023] R¹ and R² taken together with the carbon to which they areattached form C₃-C₁₀ cycloalkyl;

[0024] R³ and R⁴ are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR⁹, NR⁹R¹⁰,SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein R⁹ and R¹⁰ are as defined above;or

[0025] R³ and R⁴ together form ═O, ═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or═CR¹¹R¹² ₁₂,

[0026] wherein R¹¹ and R¹² are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl,cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen,oxo, and CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above, providedthat both R³ and R⁴ cannot be OH, NH₂, and SH, or

[0027] R¹¹ and R¹² together with the nitrogen or carbon atom to whichthey are attached form a cyclic ring;

[0028] R⁵ and R⁶ are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternaryheterocycle, OR⁹, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹,

[0029] wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,quaternary heterocycle, and quaternary heteroaryl can be substitutedwith one or more substituent groups independently selected from thegroup consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle,quaternary heteroaryl, halogen, oxo, OR¹³, NR¹³R¹⁴ SR¹³ S(O)R¹³, SO₂R¹³,SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴,C(O)NR¹³R¹⁴, C(O)OM, CR¹³, NR¹³C(O)R¹⁴, NR¹³C(O)NR¹⁴R¹⁵, NR¹³CO₂R¹⁴,OC(O)R¹³, OC(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, NR¹³SONR¹⁴R¹⁵,N¹³SO₂NR¹⁴R¹⁵,P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, andN⁺R⁹R¹¹R¹²A⁻,

[0030] wherein:

[0031] A⁻ is a pharmaceutically acceptable anion and M is apharmaceutically acceptable cation,

[0032] said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, and heterocycle can be further substituted withone or more substituent groups selected from the group consisting ofOR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸,N⁺R⁷R⁸R⁹A⁻, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷R⁸,P⁺R⁷R⁸R⁹A⁻ and P(O) (OR⁷)OR⁸, and

[0033] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, and heterocycle can optionally have one or morecarbons replaced by O, NR⁷, N⁺R⁷R⁸A⁻, S, SO, SO₂, S⁺R⁷A-, PR⁷, P(O)R⁷,P⁺R⁷R⁸A-, or phenylene, and R¹³, R¹⁴, and R¹⁵ are independently selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl,polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl,alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle,heteroaryl, quaternary heterocycle, quaternary heteroaryl,heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl,quaternary heteroarylalkyl, alkylammoniumalkyl, andcarboxyalkylaminocarbonylalkyl,

[0034] wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, andpolyalkyl optionally have one or more carbons replaced by O, NR⁹,N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻, PR⁹, P⁺R⁹R¹⁰A-, P(O)R⁹, phenylene,carbohydrate, amino acid, peptide, or polypeptide, and

[0035] R¹³, R¹⁴, and R¹⁵ are optionally substituted with one or moregroups selected from the group consisting of hydroxy, amino, sulfo,carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl,quaternary heterocycle, quaternary heteroaryl, quaternaryheterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR , NR⁹R¹⁰,N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen,CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A-, S⁺R⁹R¹⁰A-, andC(O)OM,

[0036] wherein R¹⁶ and R¹⁷ are independently selected from thesubstituents constituting R⁹ and M; or

[0037] R¹³ and R¹⁴, together with the nitrogen atom to which they areattached form a mono- or polycyclic heterocycle that is optionallysubstituted with one or more radicals selected from the group consistingof oxo, carboxy and quaternary salts; or

[0038] R¹⁴ and R¹⁵, together with the nitrogen atom to which they areattached, form a cyclic ring; and

[0039] R⁷ and R⁸ are independently selected from the group consisting ofhydrogen and alkyl; and

[0040] one or more R^(x) are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl,arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl,polyether, quaternary heterocycle, quaternary heteroaryl, OR¹³, NR¹³R¹⁴,SR¹³ S(O)R¹³, S(O)²R¹³, SO₃R¹³, S⁺R¹³R¹⁴ A-, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴,NR¹⁴C(O)R¹³, C(O)OM, COR¹³, OR¹⁸, S(O)_(n)NR¹⁸, NR¹³R¹⁸, NR¹⁸OR¹⁴,N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, amino acid, peptide, polypeptide, andcarbohydrate,

[0041] wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl,heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternaryheterocycle, and quaternary heteroaryl can be further substituted withOR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN,halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻,S⁺R⁹R¹⁰A⁻, or C(O)OM, and

[0042] wherein R¹⁸ is selected from the group consisting of acyl,arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,

[0043] wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle,heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryloptionally are substituted is with one or more substituents selectedfrom the group consisting of OR⁹, NR⁹R¹⁰, N⁺, R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹,SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM,SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, and CO()OM,

[0044] wherein in R^(x), one or more carbons are optionally replaced byO, NR¹³, N⁺R¹³R¹⁴A-, S, SO, SO₂, S⁺R¹³A⁻, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A-,phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, orpolyalkyl,

[0045] wherein in said polyalkyl, phenylene, amino acid, peptide,polypeptide, and carbohydrate, one or more carbons are optionallyreplaced by 0, NR 9, N R9R10 A, S, SO, SO₂, S⁺R⁹A-, PR⁹, P⁺R⁹R¹⁰A-, orP(O)R⁹;

[0046] wherein quaternary heterocycle and quaternary heteroaryl areoptionally substituted with one or more groups selected from the groupconsisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³,NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³,P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,

[0047] provided that both R⁵ and R⁶ cannot be hydrogen, OH, or SH andwhen R⁵ is OH, R¹, R², R³, R⁴, R⁷ and R⁸ cannot be all hydrogen;

[0048] provided that when R⁵ or R⁶ is phenyl, only one of R¹ or R² is H;

[0049] provided that when q=1 and R^(x) is styryl, anilido, oranilinocarbonyl, only one of R⁵ or R⁶ is alkyl;

[0050] provided that when n is 1, R¹, R³, R⁷, and R⁸ are hydrogen, R² ishydrogen, alkyl or aryl, R⁴ is unsubstituted amino or amino substitutedwith one or more alkyl or aryl radicals, and R⁵ is hydrogen, alkyl oraryl, then R⁶ is other than hydroxy; or

[0051] a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0052] Preferably, R⁵ and R⁶ can independently be selected from thegroup consisting of H, aryl, heterocycle, quaternary heterocycle, andquaternary heteroaryl,

[0053] wherein said aryl, heteroaryl, quaternary heterocycle, andquaternary heteroaryl can be substituted with one or more substituentgroups independently selected from the group consisting of alkyl,alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl,heterocycle, arylalkyl, halogen, oxo, OR¹³, N¹³R¹⁴, SR¹³, S(O)R¹³,SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM,SO₂NR¹³R₁₄, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, NR¹³C(O)R¹⁴, NR¹³C(O)NR¹⁴R¹⁵,NR¹³CO₂R¹⁴, OC(O)R¹³, OC(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴,NR¹³SONR¹⁴R¹⁵, NR¹³SO₂NR¹⁴R¹⁵, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R15A-, P(OR¹³O)R¹⁴,S+R¹³R¹⁴A-, and N⁺R⁹R¹¹R¹²A⁻,

[0054] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, and heterocycle can optionally have one or morecarbons replaced by O, NR⁷, N⁺R⁷R⁸A-, S, SO, SO₂, S⁺R⁷A-, PR⁷, P(O)R⁷,P⁺R⁷R⁸A-, or phenylene,

[0055] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, and heterocycle can be further substituted withone or more substituent groups selected from the group consisting ofOR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸,N⁺R⁷R⁸R⁹A⁻, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷R⁸,P⁺R⁷R⁸A⁻, and P(O)(OR⁷)OR⁸.

[0056] More preferably, R⁵ or R⁶ has the formula:

—Ar—(R^(y))_(t)

[0057] wherein:

[0058] t is an integer from 0 to 5;

[0059] Ar is selected from the group consisting of phenyl, thiophenyl,pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl,anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl,isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl,and benzoisothiazolyl; and

[0060] one or more R^(y) are independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³,NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)CM, COR¹³,NR¹³C(O)R¹⁴, NR¹³R¹⁴, C(O)NR¹³R¹⁴, NR¹³CO₂R¹³, OC(O)R¹³, CC(O)NR¹³R¹⁴,NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, NR¹³SONR¹⁴R¹⁵, NR¹³SO₂NR¹⁴R¹⁵, P(O)R¹³R¹⁴,P⁺R¹³R¹⁴R¹⁵A⁻, P(R¹³)¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,

[0061] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, and heterocycle can be further substituted withone or more substituent groups selected from the group consisting ofOR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸,N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷R⁸,P⁺R⁷R⁸A⁻, and P(O)(OR⁷)OR⁸, and

[0062] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, and heterocycle can optionally have one or morecarbons replaced by O, NR⁷, N⁺R⁷R⁸A-, S, SO₂, S⁺R⁷A-, PR⁷, P(O)R⁷,P⁺R⁷R⁸A-, or phenylene.

[0063] Most preferably, R⁵ or R has the formula (II):

[0064] Another embodiment of the invention is further directed tocompounds of Formula I wherein at least one or more of the followingconditions exist:

[0065] (1) R¹ and R ² are independently selected from the groupconsisting of hydrogen and alkyl. Preferably, R¹ and R² areindependently selected from the group consisting of C₁₋₆ alkyl. Morepreferably, R¹ and R ² are the same C₁₋₆ alkyl. Still more preferably,R¹ and R ² are n-butyl; and/or

[0066] (2) R³ and R⁴ are independently selected from the groupconsisting of hydrogen and OR⁹ wherein R⁹ is defined as set forth above.Preferably, R³ is hydrogen and R⁴ is OR⁹. Still more preferably, R³ ishydrogen and R⁴ is hydroxy; and/or

[0067] (3) Rs is substituted aryl. Preferably, R⁵ is substituted phenyl.More preferably, R⁵ is phenyl substituted with a radical selected fromthe group consisting of OR¹³, NR¹³ (O)R¹⁴, NR¹³(O)NR¹⁴R¹⁵, NR¹³CO₂R¹⁴,QC(O)R¹³, OC(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, NR¹³SONR¹⁴R¹⁵, andNR¹³SO₂NR¹⁴R¹⁵ wherein R¹³, R¹⁴ and R¹⁵ are as set forth above. Stillmore preferably, R⁵ is phenyl substituted with OR¹³. Still morepreferably, R⁵ is phenyl substituted at the para or meta position withOR¹³ wherein R¹³ comprises a quaternary heterocycle, quaternaryheteroaryl or substituted amino; and/or

[0068] (4) R⁶ is hydrogen; and/or

[0069] (5) R⁷ and R⁸ are independently selected from the groupconsisting of hydrogen and alkyl. Preferably, R¹ and R² areindependently selected from the group C₁₋₆ alkyl. Still more preferably,R¹ and R² are hydrogen; and/or

[0070] (6) R^(x) is selected from the group consisting of OR¹³ and NR³R¹⁴. Preferably, R^(x) is selected from the group consisting of alkoxy,amino, alkylamino and dialkylamino. Still more preferably, R^(x) isselected from the group consisting of methoxy and dimethylamino.

[0071] Another embodiment of the invention is further directed tocompounds of formula 1:

[0072] wherein:

[0073] q is an integer from 1 to 4;

[0074] n is an integer from 0 to 2;

[0075] R¹ and R² are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy,alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl,

[0076] wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl,alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, andcycloalkyl optionally are substituted with one or more substituentsselected from the group consisting of OR⁹, NR⁹R¹⁰, NR⁺R⁹R^(w)A⁻, SR⁹,S⁺R⁹R¹⁰A⁻, P⁺R⁹R¹⁰R¹¹A⁻, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo,and CONR⁹R¹⁰,

[0077] wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl,(polyalkyl)aryl, and cycloalkyl optionally have one or more carbonsreplaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻, P⁺R⁹R¹⁰A⁻, orphenylene,

[0078] wherein R⁹, R¹⁰, and R^(w) are independently selected from thegroup consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl,carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino,heteroarylalkyl, heterocyclylalkyl, and alkylammoniumalkyl; or

[0079] R¹ and R² taken together with the carbon to which they areattached form C₃₋₁₀ cycloalkyl;

[0080] R³ and R⁴ are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR⁹, SR⁹,S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein R⁹ and R¹⁰ are as defined above; or

[0081] R³ and R⁴ together form ═O, ═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or═CR¹¹R¹²,

[0082] wherein R¹¹ and R¹² are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl,cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen,oxo, and CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above, providedthat both R³ and R⁴ cannot be OH, NH₂, and SH, or

[0083] R¹¹ and R¹² together with the nitrogen or carbon atom to whichthey are attached form a cyclic ring;

[0084] R⁵ is selected from the group consisting of H, alkyl, alkenyl,alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR⁹,SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹,

[0085] wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,quaternary heterocycle, and quaternary heteroaryl can be substitutedwith one or more substituent groups independently selected from thegroup consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle,quaternary heteroaryl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³,SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM,SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, CR¹³, NR¹³C(O)R¹⁴, NR¹³R₁₄,C(O)NR¹⁴R¹⁵, NR¹³CO₂R¹⁴, OC(O)R¹³, OC(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴,NR¹³SONR¹⁴R¹⁵, NR¹³SO₂NR¹⁴R¹⁵, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴,S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,

[0086] wherein:

[0087] A⁻ is a pharmaceutically acceptable anion and M is apharmaceutically acceptable cation,

[0088] said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, and heterocycle can be further substituted withone or more substituent groups selected from the group consisting ofOR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸,N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷R⁸,P⁺R⁷R⁸R⁹A-, and P(O)(OR⁷)OR⁸, and

[0089] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, and heterocycle can optionally have one or morecarbons replaced by O, NR⁷, N⁺R⁷R⁸A-, S, SO, SO₂, S⁺R⁷A-, PR⁷, P(O)R⁷,P⁺R⁷R⁸A-, or phenylene, and R¹³, R¹⁴, and R¹⁵ are independently selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl,polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl,alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle,heteroaryl, quaternary heterocycle, quaternary heteroaryl,heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl,quaternary heteroarylalkyl, alkylammoniumalkyl, andcarboxyalkylaminocarbonylalkyl,

[0090] wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, andpolyalkyl optionally have one or more carbons replaced by O, NR⁹,N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻, PR⁹, P⁺R⁹R¹⁰A-, P(O)R⁹, phenylene,carbohydrate, amino acid, peptide, or polypeptide, and

[0091] R¹³, R¹⁴, and R¹⁵ are optionally substituted with one or moregroups selected from the group consisting of hydroxy, amino, sulfo,carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl,quaternary heterocycle, quaternary heteroaryl, quaternaryheterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR⁹, NR⁹R¹⁰,N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen,CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A-, S⁺R⁹R¹⁰A-, andC(O)OM,

[0092] wherein R¹⁶ and R¹⁷ are independently selected from thesubstituents constituting R⁹ and M; or

[0093] R¹³ and R¹⁴, together with the nitrogen atom to which they areattached form a mono- or polycyclic heterocycle that is optionallysubstituted with one or more radicals selected from the group consistingof oxo, carboxy and quaternary salts; or

[0094] R¹⁴ and R¹⁵, together with the nitrogen atom to which they areattached, form a cyclic ring; and

[0095] R⁶ is hydroxy; and

[0096] R⁷ and R⁸ are independently selected from the group consisting ofhydrogen and alkyl; and

[0097] one or more R^(x) are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl,arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl,polyether, quaternary heterocycle, quaternary heteroaryl, OR¹³, NR¹³R¹⁴,SR¹³, S(O)R¹³, S(O)₂R¹³, SO₃R¹³, S⁺R¹³R¹⁴A-, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴,NR¹⁴C(O)R¹³, C(O)OM, COR¹³, OR¹⁸, S(O)_(n)NR¹⁸, NR¹³R¹⁸, NR¹⁸OR¹⁴,N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, amino acid, peptide, polypeptide, andcarbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl,polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether,quaternary heterocycle, and quaternary heteroaryl can be furthersubstituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹,oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷,P⁺R^(9R) ¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and

[0098] wherein R18 is selected from the group consisting of acyl,arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,

[0099] wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle,heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryloptionally are substituted with one or more substituents selected fromthe group consisting of OR, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹,SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM, SO₂NR⁹R¹⁰,PO(OR¹⁶)OR¹⁷, and C(O)OM,

[0100] wherein in R^(x), one or more carbons are optionally replaced byO, NR¹³, N⁺R¹³R¹⁴A-, S, SO, SO₂, S⁺R¹³A⁻, PR¹, P(O)R¹³, P⁺R⁹R¹⁰A-,phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, orpolyalkyl,

[0101] wherein in said polyalkyl, phenylene, amino acid, peptide,polypeptide, and carbohydrate, one or more carbons are optionallyreplaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A-, PR⁹, P^(+R) ⁹R¹⁰A-,or P(O)R⁹;

[0102] wherein quaternary heterocycle and quaternary heteroaryl areoptionally substituted with one or more groups selected from the groupconsisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³,NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R₁₄, C(O)NR³R¹⁴, C(O)OM, COR¹³,P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,

[0103] provided that both R⁵ and R⁶ cannot be hydrogen, OH, or SH;

[0104] provided that when R⁵ is phenyl, only one of R¹ or R² is H; or

[0105] a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0106] The invention is further directed to a compound selected fromamong:

R²⁰−R¹⁹−R²¹ (Formula DI)

[0107]

[0108] wherein R¹⁹ is selected from the group consisting of alkane diyl,alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl,polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide,wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxydiyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid,peptide, and polypeptide can optionally have one or more carbon atomsreplaced by O, NR⁷, N⁺R⁷R⁸, S, SO, SO₂, S⁺R⁷R⁸, PR⁷, P⁺R⁷R⁸, phenylene,heterocycle, quatarnary heterocycle, quaternary heteroaryl, or aryl,

[0109] wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl,alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid,peptide, and polypeptide can be substituted with one or more substituentgroups independently selected from the group consisting of alkyl,alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl,heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³,SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM,SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A-,P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,

[0110] wherein R¹⁹ further comprises functional linkages by which R¹⁹ isbonded to R²⁰, R²¹, or R²² in the compounds of Formulae DII and DIII,and R²³ in the compounds of Formula DIII. Each of R²⁰, R²¹, or R²² andR²³ comprises a benzothiepine moiety as described above that istherapeutically effective in inhibiting ileal bile acid transport.

[0111] The invention is also directed to a compound selected from amongFormula DI, Formula DII and Formula DIII in which each of R²⁰, R²¹, R²²and R²³ comprises a benzothiepine moiety corresponding to the Formula:

[0112] wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R^(x), q, and n are asdefined in Formula I as described above, and R⁵⁵ is either a covalentbond or arylene.

[0113] In compounds of Formula DIV, it is particularly preferred thateach of R²⁰, R²¹, and R²² in Formulae DII 15 and DIII, and R²³ inFormula DIII, be bonded at its 7- or 8-position to R¹⁹. In compounds ofFormula DIVA, it is particularly preferred that R⁵⁵ comprise a phenylenemoiety bonded at a m- or p-carbon thereof to R¹⁹.

[0114] Examples of Formula DI include:

[0115] In any of the dimeric or multimeric structures discussedimmediately above, benzothiepine compounds of the present invention canbe used alone or in various combinations.

[0116] In any of the compounds of the present invention, R¹ and R² canbe ethyl/butyl or butyl/butyl.

[0117] In another aspect, the present invention provides apharmaceutical composition for the prophylaxis or treatment of a diseaseor condition for which a bile acid transport inhibitor is indicated,such as a hyperlipidemic condition, for example, atherosclerosis. Suchcompositions comprise any of the compounds disclosed above, alone or incombination, in an amount effective to reduce bile acid levels in theblood, or to reduce transport thereof across digestive system membranes,and a pharmaceutically acceptable carrier, excipient, or diluent.

[0118] In a further aspect, the present invention also provides a methodof treating a disease or condition in mammals, including humans, forwhich a bile acid transport inhibitor is indicated, comprisingadministering to a patient in need thereof a compound of the presentinvention in an effective amount in unit dosage form or in divideddoses.

[0119] In yet a further aspect, the present invention also providesprocesses for the preparation of compounds of the present invention.

[0120] Further scope of the applicability of the present invention willbecome apparent from the detailed description provided below. However,it should be understood that the following detailed dscription andexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only since various changes andmodifications within the spirit and scope of the invention will beomceapparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE INVENTION

[0121] The following detailed description is provided to aid thoseskilled in the art in practicing the present invention. Even so, thisdetailed description should not be construed to unduly limit the presentinvention as modifications and variations in the emobodiments discussedherein can be made by those of ordinary skill in the art withoutdeparting from the spirit or scope of the present inventive discovery.

[0122] The contents of each of the references cited herein, includingthe contents of the references cited within these primary references,are herein incorporated by reference in their entirety.

[0123] Definitions

[0124] In order to aid the reader in understanding the followingdetailed description, the following definitions are provided:

[0125] “Alkyl”, “alkenyl,” and “alkynyl” unless otherwise noted are eachstraight chain or branched chain hydrocarbons of from one to twentycarbons for alkyl or two to twenty carbons for alkenyl and alkynyl inthe present invention and therefore mean, for example, methyl, ethyl,propyl, butyl, pentyl or hexyl and ethenyl, propenyl, butenyl, pentenyl,or hexenyl and ethynyl, propynyl, butynyl, pentynyl, or hexynylrespectively and isomers thereof.

[0126] “Aryl” means a fully unsaturated mono- or multi-ring carbocyle,including, but not limited to, substituted or unsubstituted phenyl,naphthyl, or anthracenyl.

[0127] “Heterocycle” means a saturated or unsaturated mono- ormulti-ring carbocycle wherein one or more carbon atoms can be replacedby N, S, P, or O. This includes, for example, the following structures:

[0128] wherein Z, Z′, Z″ or Z′″ is C, S, P, O, or N, with the provisothat one of Z, Z′, Z″ or Z′″ is other than carbon, but is not O or Swhen attached to another Z atom by a double bond or when attached toanother O or S atom. Furthermore, the optional substituents areunderstood to be attached to Z, Z′, Z″ or Z′″ only when each is C.

[0129] The term “heteroaryl” means a fully unsaturated heterocycle.

[0130] In either “heterocycle” or “heteroaryl,” the point of attachmentto the molecule of interest can be at the heteroatom or elsewhere withinthe ring.

[0131] The term “quaternary heterocycle” means a heterocycle in whichone or more of the heteroatoms, for example, O, N, S, or P, has such anumber of bonds that it is positively charged. The point of attachmentof the quaternary heterocycle to the molecule of interest can be at aheteroatom or elsewhere.

[0132] The term “quaternary heteroaryl” means a heteroaryl in which oneor more of the heteroatoms, for example, O, N, S, or P, has such anumber of bonds that it is positively charged. The point of attachmentof the quaternary heteryaryl to the molecule of interest can be at aheteroatom or elsewhere.

[0133] The term “halogen” means a fluoro, chloro, bromo or iodo group.

[0134] The term “haloalkyl” means alkyl substituted with one or morehalogens.

[0135] The term “cycloalkyl” means a mono- or multi-ringed carbocyclewherein each ring contains three to ten carbon atoms, and wherein anyring can contain one or more double or triple bonds. Examples includeradicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloalkenyl, and cycloheptyl. The term “cycloalkyl” additionallyencompasses Spiro systems wherein the cycloalkyl ring has a carbon ringatom in common with the seven-membered heterocyclic ring of thebenzothiepine.

[0136] The term “diyl” means a diradical moiety wherein said moiety hastwo points of attachment to molecules of interest.

[0137] The term “oxo” means a doubly bonded oxygen.

[0138] The term “polyalkyl” means a branched or straight hydrocarbonchain having a molecular weight up to about 20,000, more preferably upto about 10,000, most preferably up to about 5,000.

[0139] The term “polyether” means a polyalkyl wherein one or morecarbons are replaced by oxygen, wherein the polyether has a molecularweight up to about 20,000, more preferably up to about 10,000, mostpreferably up to about 5,000.

[0140] The term “polyalkoxy” means a polymer of alkylene oxides, whereinthe polyalkoxy has a molecular weight up to about 20,000, morepreferably up to about 10,000, most preferably up to about 5,000.

[0141] The term “cycloaklylidene” means a mono- or multi-ringedcarbocycle wherein a carbon within the ring structure is doubly bondedto an atom which is not within the ring structures.

[0142] The term “carbohydrate” means a mono-, di-, tri-, orpolysaccharide wherein the polysaccharide can have a molecular weight ofup to about 20,000, for example, hydroxypropyl-methylcellulose orchitosan.

[0143] The term “peptide” means polyamino acid containing up to about100 amino acid units.

[0144] The term “polypeptide” means polyamino acid containing from about100 amino acid units to about 1000 amino acid units, more preferablyfrom about 100 amino acid units to about 750 amino acid untis, mostpreferably from about 100 amino acid units to about 500 amino acidunits.

[0145] The term “alkylammoniumalkyl” means a NH₂ group or a mono-, di-or tri-substituted amino group, any of which is bonded to an alkylwherein said alkyl is bonded to the molecule of interest.

[0146] The term “triazolyl” includes all positional isomers. In allother heterocycles and heteroaryls which contain more than one ringheteroatom and for which isomers are possible, such isomers are includedin the definition of said heterocycles and heteroaryls.

[0147] The term “sulfo” means a sulfo group, —SO₃H, or its salts.

[0148] The term “sulfoalkyl” means an alkyl group to which a sulfonategroup is bonded, wherein said alkyl is bonded to the molecule ofinterest.

[0149] The term “arylalkyl” means an aryl-substituted alkyl radical suchas benzyl. The term

[0150] “alkylarylalkyl” means an arylalkyl radical that is substitutedon the aryl group with one or more alkyl groups.

[0151] The term “heterocyclylalkyl” means an alkyl radical that issubstituted with one or more heterocycle groups. Preferableheterocyclylalkyl radicals are “lower heterocyclylalkyl” radicals havingone or more heterocycle groups attached to an alkyl radical having oneto ten carbon atoms.

[0152] The term “heteroarylalkyl” means an alkyl radical that issubstituted with one or more heteroaryl groups. Preferableheteroarylalkyl radicals are “lower heteroarylalkyl” radicals having oneor more heteroaryl groups attached to an alkyl radical having one to tencarbon atoms.

[0153] The term “quaternary heterocyclylalkyl” means an alkyl radicalthat is substituted with one or more quaternary heterocycle groups.Preferable quaternary heterocyclylalkyl radicals are “lower quaternaryheterocyclylalkyl” radicals having one or more quaternary heterocyclegroups attached to an alkyl radical having one to ten carbon atoms.

[0154] The term “quaternary heteroarylalkyl” means an alkyl radical thatis substituted with one or more quaternary heteroaryl groups. Preferablequaternary heteroarylalkyl radicals are “lower quaternaryheteroarylalkyl” radicals having one or more quaternary heteroarylgroups attached to an alkyl radical having one to ten carbon atoms.

[0155] The term “alkylheteroarylalkyl” means a heteroarylalkyl radicalthat is substituted with one or more alkyl groups. Preferablealkylheteroarylalkyl radicals are “lower alkylheteroarylalkyl” radicalswith alkyl portions having one to ten carbon atoms.

[0156] The term “alkoxy” an alkyl radical which is attached to theremainder of the molecule by oxygen, such as a methoxy radical. Morepreferred alkoxy radicals are “lower alkoxy” radicals having one to sixcarbon atoms. Examples of such radicals include methoxy, ethoxy,propoxy, iso-propoxy, butoxy and tert-butoxy.

[0157] The term “carboxy” means the carboxy group, —CO₂H, or its salts.

[0158] The term “carboxyalkyl” means an alkyl radical that issubstituted with one or more carboxy groups. Preferable carboxyalkylradicals are “lower carboxyalkyl” radicals having one or more carboxygroups attached to an alkyl radical having one to six carbon atoms.

[0159] The term “carboxyheterocycle” means a heterocycle radical that issubstituted with one or more carboxy groups.

[0160] The term “carboxyheteroaryl” means a heteroaryl radical that issubstituted with one or more carboxy groups.

[0161] The term “carboalkoxyalkyl” means an alkyl radical that issubstituted with one or more alkoxycarbonyl groups. Preferablecarboalkoxyalkyl radicals are “lower carboalkoxyalkyl” radicals havingone or more alkoxycarbonyl groups attached to an alkyl radical havingone to six carbon atoms.

[0162] The term “carboxyalkylamino” means an amino radical that is mono-or di-substituted with carboxyalkyl. Preferably, the carboxyalkylsubstituent is a “lower carboxyalkyl” radical wherein the carboxy groupis attached to an alkyl radical having one to six carbon atoms.

[0163] The term “active compound” means a compound of the presentinvention which inhibits transport of bile acids.

[0164] When used in combination, for example “alkylaryl” or “arylalkyl,”the individual terms listed above have the meaning indicated above.

[0165] The term “a bile acid transport inhibitor” means a compoundcapable of inhibiting absorption of bile acids from the intestine intothe circulatory system of a mammal, such as a human. This includesincreasing the fecal excretion of bile acids, as well as reducing theblood plasma or serum concentrations of cholesterol and cholesterolester, and more specifically, reducing LDL and VLDL cholesterol.Conditions or diseases which benefit from the prophylaxis or treatmentby bile acid transport inhibition include, for example, a hyperlipidemiccondition such as atherosclerosis.

[0166] Compounds

[0167] The compounds of the present invention can have at least twoasymmetrical carbon atoms, and therefore include racemates andstereoisomers, such as diastereomers and enantiomers, in both pure formand in admixture. Such stereoisomers can be prepared using conventionaltechniques, either by reacting enantiomeric starting materials, or byseparating isomers of compounds of the present invention.

[0168] Isomers may include geometric isomers, for example cis isomers ortrans isomers across a double bond. All such isomers are contemplatedamong the compounds of the present invention.

[0169] The compounds of the present invention also include tautomers.

[0170] The compounds of the present invention as discussed below includetheir salts, solvates and prodrugs.

[0171] Compound Syntheses

[0172] The starting materials for use in the preparation of thecompounds of the invention are known or can be prepared by conventionalmethods known to a skilled person or in an analogous manner to processesdescribed in the art.

[0173] Generally, the compounds of the present invention can be preparedby the procedures described below.

[0174] For example, as shown in Scheme I, reaction of aldehyde II withformaldehyde and sodium hydroxide yields the hydroxyaldehyde III whichis converted to mesylate IV with methansulfonyl chloride andtriethylamine similar to the procedure described in Chem. Ber. 98,728-734 (1965). Reaction of mesylate IV with thiophenol V, prepared bythe procedure described in WO 93/16055, in the presence of triethylamineyields keto-aldehyde VI which can be cyclized with the reagent, preparedfrom zinc and titanium trichloride in refluxing ethylene glycol dimethylether (DME), to give a mixture of 2,3-dihydrobenzothiepine VII and tworacemic steroisomers of benzothiepin-(5H)-4-one VIII when R¹ and R² arenonequivalent. Oxidation of VII with 3 equivalents ofm-chloro-perbenzoic acid (MCPBA) gives isomeric sulfone-epoxides IXwhich upon hydrogenation with palladium on carbon as the catalyst yielda mixture of four racemic stereoisomers of4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxides X and two racemicstereoisomers of 2,3,4,5-tetrahydrobenzothiepine-1,1-dioxides XI when R¹and R² are nonequivalent.

[0175] Optically active compounds of the present invention can beprepared by using optically active starting material III or byresolution of compounds X with optical resolution agents well known inthe art as described in J. Org. Chem., 39, 3904 (1974), ibid., 42, 2781(1977), and ibid., 44, 4891 (1979).

[0176] Alternatively, keto-aldehyde VI where R² is H can be prepared byreaction of thiophenol V with a 2-substituted acrolein.

[0177] Benzothiepin-(5H)-4-one VIII can be oxidized with MCPBA to givethe benzothiepin-(5H)-4-one-1,1-dioxide XII which can be reduced withsodium borohydride to give four racemic stereoisomers of X. The twostereoisomers of X, Xa and Xb, having the OH group and R⁵ on theopposite sides of the benzothiepine ring can be converted to the othertwo isomers of X, Xc and Xd, having the OH group and R⁵ on the same sideof the benzothiepine ring by reaction in methylene chloride with 40-50%sodium hydroxide in the presence of a phase transfer catalyst (PTC). Thetransformation can also be carried out with potassium t-butoxide in THF.

[0178] The compounds of the present invention where R⁵ is OR, NRR′ andS(O)_(n)R and R⁴ is hydroxy can be prepared by reaction of epoxide IXwhere R⁵ is H with thiol, alcohol, and amine in the presence of a base.

[0179] Another route to Xc and Xd of the present invention is shown inScheme 2. Compound VI is oxidized to compound XIII with two equivalentof m-chloroperbenzoic acid. Hydrogenolysis of compound XIII withpalladium on carbon yields compound XIV which can be cyclized witheither potassium t-butoxide or sodium hydroxide under phase transferconditions to a mixture of Xc and Xd. Separation of Xc and Xd can beaccomplished by either HPLC or fractional crystallization.

[0180] The thiophenols XVIII and V used in the present invention canalso be prepared according to the Scheme 3. Alkylation of phenol XV withan arylmethyl chloride in a nonpolar solvent according to the procedurein J. Chem. Soc., 2431-2432 (1958) gives the ortho substituted phenolXVI. The phenol XVI can be converted to the thiophenol XVIII via thethiocarbamate XVII by the procedure described in J. Org. Chem., 31, 3980(1966). The phenol XVI is first reacted with dimethyl thiocarbamoylchloride and triethylamine to give thiocarbamate XVII which is thermallyrearranged at 200-300 ° C., and the rearranged product is hydrolyzedwith sodium hydroxide to yield the thiophenol XVIII. Similarly,Thiophenol V can also be prepared from 2-acylphenol XIX via theintermediate thiocarbamate XX.

[0181] Scheme 4 shows another route to benzothiepine-1,1-dioxides Xc andXd starting from the thiophenol XVIII. Compound XVIII can be reactedwith mesylate IV to give the sulfide-aldehyde XXI. Oxidation of XXI withtwo equivalents of MCPBA yields the sulfone-aldehyde XIV which can becyclized with potassium t-butoxide to a mixture of Xc and Xd.Cyclyzation of sulfide-aldehyde with potassium t-butoxide also gives amixture of benzothiepine XXIIc and XXIId.

[0182] Examples of amine- and hydroxylamine-containing compounds of thepresent invention can be prepared as shown in Scheme 5 and Scheme 6.2-Chloro-4-nitrobenzophenone is reduced with triethylsilane andtrifluoromethane sulfonic acid to 2-chloro-4-nitrodiphenylmethane 32.Reaction of 32 with lithium sulfide followed by reacting the resultingsulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation ofXXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV which canbe reduced by hydrogenation to the hydroxylamine XXV. Protecting thehydroxylamine XXV with di-t-butyldicarbonate gives theN,O-di-(t-butoxycarbonyl)hydroxylamino derivative XXVI. Cyclization ofXXVI with potassium t-butoxide and removal of the t-butoxycarbonylprotecting group gives a mixture of hydroxylamino derivatives XXVIIc andXXVIId. The primary amine XXXIIIc and XXXIIId derivatives can also beprepared by further hydrogenation of XXIV or XXVIIc and XXVIId.

[0183] In Scheme 6, reduction of the sulfone-aldehyde XXV with hydrogenfollowed by reductive alkylation of the resulting amino derivative withhydrogen and an aldehyde catalyzed by palladium on carbon in the samereaction vessel yields the substituted amine derivative XXVIII.Cyclization of XXVIII with potassium t-butoxide yields a mixture ofsubstituted amino derivatives of this invention XXIXc and XXIXd.

[0184] Scheme 7 describes one of the methods of introducing asubstituent to the aryl ring at the 5-position of benzothiepine.Iodination of 5-phenyl derivative XXX with iodine catalyzed by mercurictriflate gives the iodo derivative XXXI, which upon palladium-catalyzedcarbonylation in an alcohol yields the carboxylate XXXII. Hydrolysis ofthe carboxylate and derivatization of the resulting acid to acidderivatives are well known in the art.

[0185] Abbreviations used in the foregoing description have thefollowing meanings:

[0186] THF—tetrahydrofuran

[0187] PTC—phase transfer catalyst

[0188] Aliquart 336—methyltricaprylylammonium chloride

[0189] MCPBA—m-chloroperbenzoic acid

[0190] Celite—a brand of diatomaceous earth filtering aid

[0191] DMF—dimethylformamide

[0192] DME—ethylene glycol dimethyl ether

[0193] BOC—t-butoxycarbonyl group

[0194] Me—methyl

[0195] Et—ethyl

[0196] Bu—butyl

[0197] EtOAc—ethyl acetate

[0198] Et₂O—diethyl ether

[0199] CH₂Cl₂—methylene chloride

[0200] MgSO₄—magnesium sulfate

[0201] NaOH—sodium hydroxide

[0202] CH₃OH—methanol

[0203] HCl—hydrochloric acid

[0204] NaCl—sodium chloride

[0205] NaH—sodium hydride

[0206] LAH—lithium aluminum hydride

[0207] LiOH—lithium hydroxide

[0208] Na₂SO₃—sodium sulfite

[0209] NaHCO₃—sodium bicarbonate

[0210] DMSO—dimethylsulfoxide

[0211] KOSiMe₃—potassium trimethylsilanolate

[0212] PEG—polyethylene glycol

[0213] MS—mass spectrometry

[0214] HRMS—high resolution mass spectrometry

[0215] ES—electrospray

[0216] NMR—nuclear magnetic resonance spectroscopy

[0217] GC—gas chromatography

[0218] MPLC—medium pressure liquid chromatography

[0219] HPLC—high pressure liquid chromatography

[0220] RPHPLC—reverse phase high pressure liquid chromatography

[0221] RT—room temperature

[0222] h or hr—hour(s)

[0223] min—minute(s)

[0224] “Enantiomerically-enriched” (e.e.) means that one enantiomer orset of diastereomers preponderates over the complementary enantiomer orset of diastereomers. Enantiomeric enrichment of a mixture ofenantiomers is calculated by dividing the concentration of thepreponderating enantiomer by the concentration of the other enantiomer,multiplying the dividend by 100, and expressing the result as a percent.Enantiomeric enrichment can be from about 1% to about 100%, aidpreferably from about 10% to about 100%, and more preferably from about20% to 100%.

[0225] R¹ and R² can be selected from among substituted andunsubstituted C₁ to C₁₀ alkyl wherein the substituent(s) can be selectedfrom among alkylcarbonyl, alkoxy, hydroxy, and nitrogen-containingheterocycles joined to the C₁ to C₁₀ alkyl through an ether linkage.Substituents at the 3-carbon can include ethyl, n-propyl, n-butyl,n-pentyl, isobutyl, isopropyl, —CH₂C(═O)C₂H₅, —CH₂OC₂H₅, and —CH₂O—(4-picoline). Ethyl, n-propyl, n-butyl, and isobutyl are preferred. Incertain particularly preferred compounds of the present invention,substituents R¹ and R²are identical, for example n-butyl/n-butyl, sothat the compound is achiral at the 3-carbon. Eliminating opticalisomerism at the 3-carbon simplifies the selection, synthesis,separation, and quality control of the compound used as an ileal bileacid transport inhibitor. In both compounds having a chiral 3-carbon andthose having an achiral 3-carbon, substituents (R^(x)) on the benzo-ring can include hydrogen, aryl, alkyl, hydroxy, halo, alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy,(N)-hydroxy-carbonylalkyl amine, haloalkylthio, halcalkylsulfinyl,haloalkylsufonyl, amino, N-alkylamino, N,N-dialkylamino,(N)-alkoxycarbamoyl, (N)-aryloxycarbamoyl, (N)-aralkyloxycarbamoyl,trialkylammonium (especially with a halide counterion), (N)-amido,(N)-alkylamido, -N-alkylamido, -N,N-dialkylamido, (N)-haloalkylamido,(N)-sulfonamido, (N)-alkylsulfonamido, (N)-haloalkylsulfonamido,carboxyalkyl-amino, trialkylammonium salt, (N)-carbamic acid, alkyl orbenzyl ester, N-acylamine, hydroxylamine, haloacylamine, carbohydrate,thiophene a trialkyl ammonium salt having a carboxylic acid or hydroxysubstituent on one or more of the alkyl substituents, an alkylene bridgehaving a quaternary ammonium salt substituted thereon,—[O(CH₂)_(w)]_(x)-X where x is 2 to 12, w is 2 or 3 and X is a halo or aquaternary ammonium salt, and (N)-nitrogen containing heterocyclewherein the nitrogen of said heterocycle is optionally quaternized.Among the preferred species which may constitute Rx are methyl, ethyl,isopropyl, t-butyl, hydroxy, methoxy, ethoxy, isopropoxy, methylthio,iodo, bromo, fluoro, methylsulfinyl, methylsulfonyl, ethylthio, amino,hydroxylamine, N-methylamino, N,N-dimethylamino, N,N-diethylamino,(N)-benzyloxycarbamoyl, trimethylammonium, A⁻, —NHC(═O)CH₃,—NHC(═O)C₅H₁₁, —NHC(═O)C₆HI₁₃, carboxyethylamino, (N) -morpholinyl, (N)-azetidinyl, (N)-N-methylazetidinium A⁻, (N)-pyrrolidinyl, pyrrolyl,(N)-N-methylpyridinium A⁻, (N)-N-methylmorpholinium A⁻, andN-N′-methylpiperazinyl, (N)-bromomethylamido, (N)-N-hexylamino,thiophene, —N⁺ (CH₃)₂CO₂H I⁻, —NCH₃CH₂CO₂H, —(N)-N′-dimethylpiperaziniumI⁻, (N)-t-butyloxycarbamoyl, (N)-methylsulfonamido,(N)N′-methylpyrrolidinium, and —(OCH₂CH₂)₃I, where A⁻ is apharmaceutically acceptable anion. The benzo ring is can bemono-substituted at the 6, 7 or 8 position, or disubstituted at the 7-and -8 positions. Also included are the 6,7,8-trialkoxy compounds, forexample the 6,7,8-trimethoxy compounds. A variety of other substituentscan be advantageously present on the 6, 7, 8, and/or 9- positions of thebenzo ring, including, for example, guanidinyl, cycloalkyl, carbohydrate(e.g., a 5 or 6 carbon monosaccharide), peptide, and quaternary ammoniumsalts linked to the ring via poly(oxyalkylene) linkages, e.g.,—(OCH₂CH₂)_(x)—N⁺R¹³R¹⁴R¹⁵A⁻ , where x is 2 to 10. Exemplary compoundsare those set forth below in Table 1. TABLE 1 Alternative Compounds #3(Family F101.xxx.yyy)

Prefix (FFF.xxx.yyy) Cpd# R¹═R² R⁵ (R^(x))q F101.001 01 ethyl Ph—7-methyl 02 ethyl Ph— 7-ethyl 03 ethyl Ph— 7-iso-propyl 04 ethyl Ph—7-tert-butyl 05 ethyl Ph— 7-OH 06 ethyl Ph— 7-OCH₃ 07 ethyl Ph—7-O-(iso-propyl) 08 ethyl Ph— 7-SCH₃ 09 ethyl Ph— 7-SOCH₃ 10 ethyl Ph—7-SO₂CH₃ 11 ethyl Ph— 7-SCH₂CH₃ 12 ethyl Ph— 7-NH₂ 13 ethyl Ph— 7-NHOH14 ethyl Ph— 7-NHCH₃ 15 ethyl Ph— 7-N(CH₃)₂ 16 ethyl Ph— 7-N⁺(CH₃)₃, I⁻17 ethyl Ph— 7-NHC(═O)CH₃ 18 ethyl Ph— 7-N(CH₂CH₃)₂ 19 ethyl Ph—7-NMeCH₂CO₂H 20 ethyl Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 ethyl Ph—7-(N)-morpholine 22 ethyl Ph— 7-(N)-azetidine 23 ethyl Ph—7-(N)—N-methylazetidinium, I⁻ 24 ethyl Ph— 7-(N)-pyrrolidine 25 ethylPh— 7-(N)—N-methyl-pyrrolidinium, I⁻ 26 ethyl Ph—7-(N)—N-methyl-morpholinium, I⁻ 27 ethyl Ph— 7-(N)—N′-methylpiperazine28 ethyl Ph— 7-(N)—N′-dimethylpiperazinium, I⁻ 29 ethyl Ph— 7-NH—CBZ 30ethyl Ph— 7-NHC(O)C₅H₁₁ 31 ethyl Ph— 7-NHC(O)CH₂Br 32 ethyl Ph—7-NH—C(NH)NH₂ 33 ethyl Ph— 7-(2)-thiophene 34 ethyl Ph— 8-methyl 35ethyl Ph— 8-ethyl 36 ethyl Ph— 8-iso-propyl 37 ethyl Ph— 8-tert-butyl 38ethyl Ph— 8-OH 39 ethyl Ph— 8-OCH₃ 40 ethyl Ph— 8-O(iso-propyl) 41 ethylPh— 8-SCH₃ 42 ethyl Ph— 8-SOCH₃ 43 ethyl Ph— 8-SO₂CH₃ 44 ethyl Ph—8-SCH₂CH₃ 45 ethyl Ph— 8-NH₂ 46 ethyl Ph— 8-NHOH 47 ethyl Ph— 8-NHCH₃ 48ethyl Ph— 8-N(CH₃)₂ 49 ethyl Ph— 8-N⁺(CH₃)₃, I⁻ 50 ethyl Ph—8-NHC(═O)CH₃ 51 ethyl Ph— 8-N(CH₂CH₃)₂ 52 ethyl Ph— 8-NMeCH₂CO₂H 53ethyl Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 ethyl Ph— 8-(N)-morpholine 55 ethylPh— 8-(N)-azetidine 56 ethyl Ph— 8-(N)—N-methylazetidinium, I⁻ 57 ethylPh— 8-(N)-pyrrolidine 58 ethyl Ph— 8-(N)—N-methyl-pyrrolidinium, I⁻ 59ethyl Ph— 8-(N)—N-methyl-morpholinium, I⁻ 60 ethyl Ph—8-(N)—N′-methylpiperazine 61 ethyl Ph— 8-(N)—N′-dimethylpiperazinium, I⁻62 ethyl Ph— 8-NH—CBZ 63 ethyl Ph— 8-NHC(O)C₅H₁₁ 64 ethyl Ph—8-NHC(O)CH₂Br 65 ethyl Ph— 8-NH—C(NH)NH₂ 66 ethyl Ph— 8-(2)-thiophene 67ethyl Ph— 9-methyl 68 ethyl Ph— 9-ethyl 69 ethyl Ph— 9-iso-propyl 70ethyl Ph— 9-tert-butyl 71 ethyl Ph— 9-OH 72 ethyl Ph— 9-OCH₃ 73 ethylPh— 9-O(iso-propyl) 74 ethyl Ph— 9-SCH₃ 75 ethyl Ph— 9-SOCH₃ 76 ethylPh— 9-SO₂CH₃ 77 ethyl Ph— 9-SCH₂CH₃ 78 ethyl Ph— 9-NH₂ 79 ethyl Ph—9-NHOH 80 ethyl Ph— 9-NHCH₃ 81 ethyl Ph— 9-N(CH₃)₂ 82 ethyl Ph—9-N⁺(CH₃)₃, I⁻ 83 ethyl Ph— 9-NHC(═O)CH₃ 84 ethyl Ph— 9-N(CH₂CH₃)₂ 85ethyl Ph— 9-NMeCH₂CO₂H 86 ethyl Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 ethyl Ph—9-(N)-morpholine 88 ethyl Ph— 9-(N)-azetidine 89 ethyl Ph—9-(N)—N-methylazetidinium, I⁻ 90 ethyl Ph— 9-(N)-pyrrolidine 91 ethylPh— 9-(N)—N-methyl-pyrrolidinium, I⁻ 92 ethyl Ph—9-(N)—N-methylmorpholinium, I⁻ 93 ethyl Ph— 9-(N)—N′-methylpiperazine 93ethyl Ph— 9-(N)—N′-dimethylpiperazinium, I⁻ 95 ethyl Ph— 9-NH—CBZ 96ethyl Ph— 9-NHC(O)C₅H₁₁ 97 ethyl Ph— 9-NHC(O)CH₂Br 98 ethyl Ph—9-NH—C(NH)NH₂ 99 ethyl Ph— 9-(2)-thiophene 100 ethyl Ph— 7-OCH₃, 8-OCH₃101 ethyl Ph— 7-SCH₃, 8-OCH₃ 102 ethyl Ph— 7-SCH₃, 8-SCH₃ 103 ethyl Ph—6-OCH₃, 7-OCH₃, 8-OCH₃ F101.002 01 n-propyl Ph— 7-methyl 02 n-propyl Ph—7-ethyl 03 n-propyl Ph— 7-iso-propyl 04 n-propyl Ph— 7-tert-butyl 05n-propyl Ph— 7-OH 06 n-propyl Ph— 7-OCH₃ 07 n-propyl Ph— 7-O(iso-propyl)08 n-propyl Ph— 7-SCH₃ 09 n-propyl Ph— 7-SOCH₃ 10 n-propyl Ph— 7-SO₂CH₃11 n-propyl Ph— 7-SCH₂CH₃ 12 n-propyl Ph— 7-NH₂ 13 n-propyl Ph— 7-NHOH14 n-propyl Ph— 7-NHCH₃ 15 n-propyl Ph— 7-N(CH₃)₂ 16 n-propyl Ph—7-N⁺(CH₃)₃, I⁻ 17 n-propyl Ph— 7-NHC(═O)CH₃ 18 n-propyl Ph— 7-N(CH₂CH₃)₂19 n-propyl Ph— 7-NMeCH₂CO₂H 20 n-propyl Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21n-propyl Ph— 7-(N)-morpholine 22 n-propyl Ph— 7-(N)-azetidine 23n-propyl Ph— 7-(N)—N-methylazetidinium, I⁻ 24 n-propyl Ph—7-(N)-pyrrolidine 25 n-propyl Ph— 7-(N)—N-methyl-pyrrolidinium, I⁻ 26n-propyl Ph— 7-(N)—N-methyl-morpholinium, I⁻ 27 n-propyl Ph—7-(N)—N′-methylpiperazine 28 n-propyl Ph— 7-(N)—N′-dimethylpiperazinium,I⁻ 29 n-propyl Ph— 7-NH—CBZ 30 n-propyl Ph— 7-NHC(O)C₅H₁₁ 31 n-propylPh— 7-NHC(O)CH₂Br 32 n-propyl Ph— 7-NH—C(NH)NH₂ 33 n-propyl Ph—7-(2)-thiophene 34 n-propyl Ph— 8-methyl 35 n-propyl Ph— 8-ethyl 36n-propyl Ph— 8-iso-propyl 37 n-propyl Ph— 8-tert-butyl 38 n-propyl Ph—8-OH 39 n-propyl Ph— 8-OCH₃ 40 n-propyl Ph— 8-O(iso-propyl) 41 n-propylPh— 8-SCH₃ 42 n-propyl Ph— 8-SOCH₃ 43 n-propyl Ph— 8-SO₂CH₃ 44 n-propylPh— 8-SCH₂CH₃ 45 n-propyl Ph— 8-NH₂ 46 n-propyl Ph— 8-NHOH 47 n-propylPh— 8-NHCH₃ 48 n-propyl Ph— 8-N(CH₃)₂ 49 n-propyl Ph— 8-N⁺(CH₃)₃, I⁻ 50n-propyl Ph— 8-NHC(═O)CH₃ 51 n-propyl Ph— 8-N(CH₂CH₃)₂ 52 n-propyl Ph—8-NMeCH₂CO₂H 53 n-propyl Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 n-propyl Ph—8-(N)-morpholine 55 n-propyl Ph— 8-(N)-azetidine 56 n-propyl Ph—8-(N)—N-methylazetidinium, I⁻ 57 n-propyl Ph— 8-(N)-pyrrolidine 58n-propyl Ph— 8-(N)—N-methyl-pyrrolidinium, I⁻ 59 n-propyl Ph—8-(N)—N-methyl-morpholinium, I⁻ 60 n-propyl Ph—8-(N)—N′-methylpiperazine 61 n-propyl Ph— 8-(N)—N′-dimethylpiperazinium,I⁻ 62 n-propyl Ph— 8-NH—CBZ 63 n-propyl Ph— 8-NHC(O)C₅H₁₁ 64 n-propylPh— 8-NHC(O)CH₂Br 65 n-propyl Ph— 8-NH—C(NH)NH₂ 66 n-propyl Ph—8-(2)-thiophene 67 n-propyl Ph— 9-methyl 68 n-propyl Ph— 9-ethyl 69n-propyl Ph— 9-iso-propyl 70 n-propyl Ph— 9-tert-butyl 71 n-propyl Ph—9-OH 72 n-propyl Ph— 9-OCH₃ 73 n-propyl Ph— 9-O(iso-propyl) 74 n-propylPh— 9-SCH₃ 75 n-propyl Ph— 9-SOCH₃ 76 n-propyl Ph— 9-SO₂CH₃ 77 n-propylPh— 9-SCH₂CH₃ 78 n-propyl Ph— 9-NH₂ 79 n-propyl Ph— 9-NHOH 80 n-propylPh— 9-NHCH₃ 81 n-propyl Ph— 9-N(CH₃)₂ 82 n-propyl Ph— 9-N⁺(CH₃)₃, I⁻ 83n-propyl Ph— 9-NHC(═O)CH₃ 84 n-propyl Ph— 9-N(CH₂CH₃)₂ 85 n-propyl Ph—9-NMeCH₂CO₂H 86 n-propyl Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 n-propyl Ph—9-(N)-morpholine 88 n-propyl Ph— 9-(N)-azetidine 89 n-propyl Ph—9-(N)—N-methylazetidinium, I⁻ 90 n-propyl Ph— 9-(N)-pyrrolidine 91n-propyl Ph— 9-(N)—N-methyl-pyrrolidinium, I⁻ 92 n-propyl Ph—9-(N)—N-methyl-morpholinium, I⁻ 93 n-propyl Ph—9-(N)—N′-methylpiperazine 93 n-propyl Ph— 9-(N)—N′-dimethylpiperazinium,I⁻ 95 n-propyl Ph— 9-NH—CBZ 96 n-propyl Ph— 9-NBC(O)C₅H₁₁ 97 n-propylPh— 9-NHC(O)CH₂Br 98 n-propyl Ph— 9-NH—C(NH)NH₂ 99 n-propyl Ph—9-(2)-thiophene 100 n-propyl Ph— 7-OCH₃, 8-OCH₃ 101 n-propyl Ph— 7-SCH₃,8-OCH₃ 102 n-propyl Ph— 7-SCH₃, 8-SCH₃ 103 n-propyl Ph— 6-OCH₃, 7-OCH₃,8-OCH₃ F101.003 01 n-butyl Ph— 7-methyl 02 n-butyl Ph— 7-ethyl 03n-butyl Ph— 7-iso-propyl 04 n-butyl Ph— 7-tert-butyl 05 n-butyl Ph— 7-OH06 n-butyl Ph— 7-OCH₃ 07 n-butyl Ph— 7-O(iso-propyl) 08 n-butyl Ph—7-SCH₃ 09 n-butyl Ph— 7-SOCH₃ 10 n-butyl Ph— 7-SO₂CH₃ 11 n-butyl Ph—7-SCH₂CH₃ 12 n-butyl Ph— 7-NH₂ 13 n-butyl Ph— 7-NHOH 14 n-butyl Ph—7-NHCH₃ 15 n-butyl Ph— 7-N(CH₃)₂ 16 n-butyl Ph— 7-N⁺(CH₃)₃, I⁻ 17n-butyl Ph— 7-NHC(═O)CH₃ 18 n-butyl Ph— 7-N(CH₂CH₃)₂ 19 n-butyl Ph—7-NMeCH₂CO₂H 20 n-butyl Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 n-butyl Ph—7-(N)-morpholine 22 n-butyl Ph— 7-(N)-azetidine 23 n-butyl Ph—7-(N)—N-methylazetidinium, I⁻ 24 n-butyl Ph— 7-(N)-pyrrolidine 25n-butyl Ph— 7-(N)—N-methyl-pyrrolidinium, I⁻ 26 n-butyl Ph—7-(N)—N-methyl-morpholinium, I⁻ 27 n-butyl Ph— 7-(N)—N′-methylpiperazine28 n-butyl Ph— 7-(N)—N′-dimethylpiperazinium, I⁻ 29 n-butyl Ph— 7-NH—CBZ30 n-butyl Ph— 7-NHC(O)C₅H₁₁ 31 n-butyl Ph— 7-NHC(O)CH₂Br 32 n-butyl Ph—7-NH—C(NH)NH₂ 33 n-butyl Ph— 7-(2)-thiophene 34 n-butyl Ph— 8-methyl 35n-butyl Ph— 8-ethyl 36 n-butyl Ph— 8-iso-propyl 37 n-butyl Ph—8-tert-butyl 38 n-butyl Ph— 8-OH 39 n-butyl Ph— 8-OCH₃ 40 n-butyl Ph—8-O(iso-propyl) 41 n-butyl Ph— 8-SCH₃ 42 n-butyl Ph— 8-SOCH₃ 43 n-butylPh— 8-SO₂CH₃ 44 n-butyl Ph— 8-SCH₂CH₃ 45 n-butyl Ph— 8-NH₂ 46 n-butylPh— 8-NHOH 47 n-butyl Ph— 8-NHCH₃ 48 n-butyl Ph— 8-N(CH₃)₂ 49 n-butylPh— 8-N⁺(CH₃)₃, I⁻ 50 n-butyl Ph— 8-NHC(═O)CH₃ 51 n-butyl Ph—8-N(CH₂CH₃)₂ 52 n-butyl Ph— 8-NMeCH₂CO₂H 53 n-butyl Ph—8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 n-butyl Ph— 8-(N)-morpholine 55 n-butyl Ph—8-(N)-azetidine 56 n-butyl Ph— 8-(N)—N-methylazetidinium, I⁻ 57 n-butylPh— 8-(N)-pyrrolidine 58 n-butyl Ph— 8-(N)—N-methyl-pyrrolidinium, I⁻ 59n-butyl Ph— 8-(N)—N-methyl-morpholinium, I⁻ 60 n-butyl Ph—8-(N)—N′-methylpiperazine 61 n-butyl Ph— 8-(N)—N′-dimethylpiperazinium,I⁻ 62 n-butyl Ph— 8-NH—CBZ 63 n-butyl Ph— 8-NHC(O)C₅H₁₁ 64 n-butyl Ph—8-NHC(O)CH₂Br 65 n-butyl Ph— 8-NH-C(NH)NH₂ 66 n-butyl Ph—8-(2)-thiophene 67 n-butyl Ph— 9-methyl 68 n-butyl Ph— 9-ethyl 69n-butyl Ph— 9-iso-propyl 70 n-butyl Ph— 9-tert-butyl 71 n-butyl Ph— 9-OH72 n-butyl Ph— 9-OCH₃ 73 n-butyl Ph— 9-O(iso-propyl) 74 n-butyl Ph—9-SCH₃ 75 n-butyl Ph— 9-SOCH₃ 76 n-butyl Ph— 9-SO₂CH₃ 77 n-butyl Ph—9-SCH₂CH₃ 78 n-butyl Ph— 9-NH₂ 79 n-butyl Ph— 9-NHOH 80 n-butyl Ph—9-NHCH₃ 81 n-butyl Ph— 9-N(CH₃)₂ 82 n-butyl Ph— 9-N⁺(CH₃)₃, I⁻ 83n-butyl Ph— 9-NHC(═O)CH₃ 84 n-butyl Ph— 9-N(CH₂CH₃)₂ 85 n-butyl Ph—9-NMeCH₂CO₂H 86 n-butyl Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 n-butyl Ph—9-(N)-morpholine 88 n-butyl Ph— 9-(N)-azetidine 89 n-butyl Ph—9-(N)—N-methylazetidinium, I⁻ 90 n-butyl Ph— 9-(N)-pyrrolidine 91n-butyl Ph— 9-(N)—N-methyl-pyrrolidinium, I⁻ 92 n-butyl Ph—9-(N)—N-methyl-morpholinium, I⁻ 93 n-butyl Ph— 9-(N)—N′-methylpiperazine93 n-butyl Ph— 9-(N)—N′-dimethylpiperazinium, I⁻ 95 n-butyl Ph— 9-NH—CBZ96 n-butyl Ph— 9-NHC(O)C₅H₁₁ 97 n-butyl Ph— 9-NHC(O)CH₂Br 98 n-butyl Ph—9-NH—C(NH)NH₂ 99 n-butyl Ph— 9-(2)-thiophene 100 n-butyl Ph— 7-OCH₃,8-OCH₃ 101 n-butyl Ph— 7-SCH₃, 8-OCH₃ 102 n-butyl Ph— 7-SCH₃, 8-SCH₃ 103n-butyl Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃ F101.004 01 n-pentyl Ph— 7-methyl 02n-pentyl Ph— 7-ethyl 03 n-pentyl Ph— 7-iso-propyl 04 n-pentyl Ph—7-tert-butyl 05 n-pentyl Ph— 7-OH 06 n-pentyl Ph— 7-OCH₃ 07 n-pentyl Ph—7-O(iso-propyl) 08 n-pentyl Ph— 7-SCH₃ 09 n-pentyl Ph— 7-SOCH₃ 10n-pentyl Ph— 7-SO₂CH₃ 11 n-pentyl Ph— 7-SCH₂CH₃ 12 n-pentyl Ph— 7-NH₂ 13n-pentyl Ph— 7-NHOH 14 n-pentyl Ph— 7-NHCH₃ 15 n-pentyl Ph— 7-N(CH₃)₂ 16n-pentyl Ph— 7-N⁺(CH₃)₃, I⁻ 17 n-pentyl Ph— 7-NHC(═O)CH₃ 18 n-pentyl Ph—7-N(CH₂CH₃)₂ 19 n-pentyl Ph— 7-NMeCH₂CO₂H 20 n-pentyl Ph—7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 n-pentyl Ph— 7-(N)-morpholine 22 n-pentyl Ph—7-(N)-azetidine 23 n-pentyl Ph— 7-(N)—N-methylazetidinium, I⁻ 24n-pentyl Ph— 7-(N)-pyrrolidine 25 n-pentyl Ph—7-(N)—N-methyl-pyrrolidinium, I⁻ 26 n-pentyl Ph—7-(N)—N-methyl-morpholinium, I⁻ 27 n-pentyl Ph—7-(N)—N′-methylpiperazine 28 n-pentyl Ph— 7-(N)—N′-dimethylpiperazinium,I⁻ 29 n-pentyl Ph— 7-NH—CBZ 30 n-pentyl Ph— 7-NHC(O)C₅H₁₁ 31 n-pentylPh— 7-NHC(O)CH₂Br 32 n-pentyl Ph— 7-NH—C(NH)NH₂ 33 n-pentyl Ph—7-(2)-thiophene 34 n-pentyl Ph— 8-methyl 35 n-pentyl Ph— 8-ethyl 36n-pentyl Ph— 8-iso-propyl 37 n-pentyl Ph— 8-tert-butyl 38 n-pentyl Ph—8-OH 39 n-pentyl Ph— 8-OCH₃ 40 n-pentyl Ph— 8-O(iso-propyl) 41 n-pentylPh— 8-SCH₃ 42 n-pentyl Ph— 8-SOCH₃ 43 n-pentyl Ph— 8-SO₂CH₃ 44 n-pentylPh— 8-SCH₂CH₃ 45 n-pentyl Ph— 8-NH₂ 46 n-pentyl Ph— 8-NHOH 47 n-pentylPh— 8-NHCH₃ 48 n-pentyl Ph— 8-N(CH₃)₂ 49 n-pentyl Ph— 8-N⁺(CH₃)₃, I⁻ 50n-pentyl Ph— 8-NHC(═O)CH₃ 51 n-pentyl Ph— 8-N(CH₂CH₃)₂ 52 n-pentyl Ph—8-NMeCH₂CO₂H 53 n-pentyl Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 n-pentyl Ph—8-(N)-morpholine 55 n-pentyl Ph— 8-(N)-azetidine 56 n-pentyl Ph—8-(N)—N-methylazetidinium, I⁻ 57 n-pentyl Ph— 8-(N)-pyrrolidine 58n-pentyl Ph— 8-(N)—N-methyl-pyrrolidinium, I⁻ 59 n-pentyl Ph—8-(N)—N-methyl-morpholinium, I⁻ 60 n-pentyl Ph—8-(N)—N′-methylpiperazine 61 n-pentyl Ph— 8-(N)—N′-dimethylpiperazinium,I⁻ 62 n-pentyl Ph— 8-NH—CBZ 63 n-pentyl Ph— 8-NHC(O)C₅H₁₁ 64 n-pentylPh— 8-NHC(O)CH₂Br 65 n-pentyl Ph— 8-NH—C(NH)NH₂ 66 n-pentyl Ph—8-(2)-thiophene 67 n-pentyl Ph— 9-methyl 68 n-pentyl Ph— 9-ethyl 69n-pentyl Ph— 9-iso-propyl 70 n-pentyl Ph— 9-tert-butyl 71 n-pentyl Ph—9-OH 72 n-pentyl Ph— 9-OCH₃ 73 n-pentyl Ph— 9-O(iso-propyl) 74 n-pentylPh— 9-SCH₃ 75 n-pentyl Ph— 9-SOCH₃ 76 n-pentyl Ph— 9-SO₂CH₃ 77 n-pentylPh— 9-SCH₂CH₃ 78 n-pentyl Ph— 9-NH₂ 79 n-pentyl Ph— 9-NHOH 80 n-pentylPh— 9-NHCH₃ 81 n-pentyl Ph— 9-N(CH₃)₂ 82 n-pentyl Ph— 9-N⁺(CH₃)₃, I⁻ 83n-pentyl Ph— 9-NHC(═O)CH₃ 84 n-pentyl Ph— 9-N(CH₂CH₃)₂ 85 n-pentyl Ph—9-NMeCH₂CO₂H 86 n-pentyl Ph— 9-N⁺(Me)_(2CH) ₂CO₂H, I⁻ 87 n-pentyl Ph—9-(N)-morpholine 88 n-pentyl Ph— 9-(N)-azetidine 89 n-pentyl Ph—9-(N)—N-methylazetidinium, I⁻ 90 n-pentyl Ph— 9-(N)-pyrrolidine 91n-pentyl Ph— 9-(N)—N-methyl-pyrrolidinium, I⁻ 92 n-pentyl Ph—9-(N)—N-methyl-morpholinium, I⁻ 93 n-pentyl Ph—9-(N)—N′-methylpiperazine 93 n-pentyl Ph— 9-(N)—N′-dimethylpiperazinium,I⁻ 95 n-pentyl Ph— 9-NH—CBZ 96 n-pentyl Ph— 9-NHC(O)C₅H₁₁ 97 n-pentylPh— 9-NHC(O)CH₂Br 98 n-pentyl Ph— 9-NH—C(NH)NH₂ 99 n-pentyl Ph—9-(2)-thiophene 100 n-pentyl Ph— 7-OCH₃, 8-OCH₃ 101 n-pentyl Ph— 7-SCH₃,8-OCH₃ 102 n-pentyl Ph— 7-SCH₃, 8-SCH₃ 103 n-pentyl Ph— 6-OCH₃, 7-OCH₃,8-OCH₃ F101.005 01 n-hexyl Ph— 7-methyl 02 n-hexyl Ph— 7-ethyl 03n-hexyl Ph— 7-iso-propyl 04 n-hexyl Ph— 7-tert-butyl 05 n-hexyl Ph— 7-OH06 n-hexyl Ph— 7-OCH₃ 07 n-hexyl Ph— 7-O(iso-propyl) 08 n-hexyl Ph—7-SCH₃ 09 n-hexyl Ph— 7-SOCH₃ 10 n-hexyl Ph— 7-SO₂CH₃ 11 n-hexyl Ph—7-SCH₂CH₃ 12 n-hexyl Ph— 7-NH₂ 13 n-hexyl Ph— 7-NHOH 14 n-hexyl Ph—7-NHCH₃ 15 n-hexyl Ph— 7-N(CH₃)₂ 16 n-hexyl Ph— 7-N⁺(CH₃)₃, I⁻ 17n-hexyl Ph— 7-NHC(═O)CH₃ 18 n-hexyl Ph— 7-N(CH₂CH₃)₂ 19 n-hexyl Ph—7-NMeCH₂CO₂H 20 n-hexyl Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 n-hexyl Ph—7-(N)-morpholine 22 n-hexyl Ph— 7-(N)-azetidine 23 n-hexyl Ph—7-(N)—N-methylazetidinium, I⁻ 24 n-hexyl Ph— 7-(N)-pyrrolidine 25n-hexyl Ph— 7-(N)—N-methyl-pyrrolidinium, I⁻ 26 n-hexyl Ph—7-(N)—N-methyl-morpholinium, I⁻ 27 n-hexyl Ph— 7-(N)—N′-methylpiperazine28 n-hexyl Ph— 7-(N)—N′-dimethylpiperazinium, I⁻ 29 n-hexyl Ph— 7-NH—CBZ30 n-hexyl Ph— 7-NHC(O)C₅H₁₁ 31 n-hexyl Ph— 7-NHC(O)CH₂Br 32 n-hexyl Ph—7-NH—C(NH)NH₂ 33 n-hexyl Ph— 7-(2)-thiophene 34 n-hexyl Ph— 8-methyl 35n-hexyl Ph— 8-ethyl 36 n-hexyl Ph— 8-iso-propyl 37 n-hexyl Ph—8-tert-butyl 38 n-hexyl Ph— 8-OH 39 n-hexyl Ph— 8-OCH₃ 40 n-hexyl Ph—8-O(iso-propyl) 41 n-hexyl Ph— 8-SCH₃ 42 n-hexyl Ph— 8-SOCH₃ 43 n-hexylPh— 8-SO₂CH₃ 44 n-hexyl Ph— 8-SCH₂CH₃ 45 n-hexyl Ph— 8-NH₂ 46 n-hexylPh— 8-NHOH 47 n-hexyl Ph— 8-NHCH₃ 48 n-hexyl Ph— 8-N(CH₃)₂ 49 n-hexylPh— 8-N⁺(CH₃)₃, I⁻ 50 n-hexyl Ph— 8-NHC(═O)CH₃ 51 n-hexyl Ph—8-N(CH₂CH₃)₂ 52 n-hexyl Ph— 8-NMeCH₂CO₂H 53 n-hexyl Ph—8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 n-hexyl Ph— 8-(N)-morpholine 55 n-hexyl Ph—8-(N)-azetidine 56 n-hexyl Ph— 8-(N)—N-methylazetidinium, I⁻ 57 n-hexylPh— 8-(N)-pyrrolidine 58 n-hexyl Ph— 8-(N)—N-methyl-pyrrolidinium, I⁻ 59n-hexyl Ph— 8-(N)—N-methyl-morpholinium, I⁻ 60 n-hexyl Ph—8-(N)—N′-methylpiperazine 61 n-hexyl Ph— 8-(N)—N′-dimethylpiperazinium,I⁻ 62 n-hexyl Ph— 8-NH—CBZ 63 n-hexyl Ph— 8-NHC(O)C₅H₁₁ 64 n-hexyl Ph—8-NHC(O)CH₂Br 65 n-hexyl Ph— 8-NH—C(NH)NH₂ 66 n-hexyl Ph—8-(2)-thiophene 67 n-hexyl Ph— 9-methyl 68 n-hexyl Ph— 9-ethyl 69n-hexyl Ph— 9-iso-propyl 70 n-hexyl Ph— 9-tert-butyl 71 n-hexyl Ph— 9-OH72 n-hexyl Ph— 9-OCH₃ 73 n-hexyl Ph— 9-O(iso-propyl) 74 n-hexyl Ph—9-SCH₃ 75 n-hexyl Ph— 9-SOCH₃ 76 n-hexyl Ph— 9-SO₂CH₃ 77 n-hexyl Ph—9-SCH₂CH₃ 78 n-hexyl Ph— 9-NH₂ 79 n-hexyl Ph— 9-NHOH 80 n-hexyl Ph—9-NHCH₃ 81 n-hexyl Ph— 9-N(CH₃)₂ 82 n-hexyl Ph— 9-N⁺(CH₃)₃, I⁻ 83n-hexyl Ph— 9-NHC(═O)CH₃ 84 n-hexyl Ph— 9-N(CH₂CH₃)₂ 85 n-hexyl Ph—9-NMeCH₂CO₂H 86 n-hexyl Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 n-hexyl Ph—9-(N)-morpholine 88 n-hexyl Ph— 9-(N)-azetidine 89 n-hexyl Ph—9-(N)—N-methylazetidine, I⁻ 90 n-hexyl Ph— 9-(N)-pyrrolidine 91 n-hexylPh— 9-(N)—N-methyl-pyrrolidinium, I⁻ 92 n-hexyl Ph—9-(N)—N-methyl-morpholinium, I⁻ 93 n-hexyl Ph— 9-(N)—N′-methylpiperazine93 n-hexyl Ph— 9-(N)—N′-dimethylpiperazinium 95 n-hexyl Ph— 9-NH—CBZ 96n-hexyl Ph— 9-NHC(O)C₅H₁₁ 97 n-hexyl Ph— 9-NHC(O)CH₂Br 98 n-hexyl Ph—9-NH—C(NH)NH₂ 99 n-hexyl Ph— 9-(2)-thiophene 100 n-hexyl Ph— 7-OCH₃,8-OCH₃ 101 n-hexyl Ph— 7-SCH₃, 8-OCH₃ 102 n-hexyl Ph— 7-SCH₃, 8-SCH₃ 103n-hexyl Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃ F101.006 01 iso-propyl Ph— 7-methyl02 iso-propyl Ph— 7-ethyl 03 iso-propyl Ph— 7-iso-propyl 04 iso-propylPh— 7-tert-butyl 05 iso-propyl Ph— 7-OH 06 iso-propyl Ph— 7-OCH₃ 07iso-propyl Ph— 7-O(iso-propyl) 08 iso-propyl Ph— 7-SCH₃ 09 iso-propylPh— 7-SOCH₃ 10 iso-propyl Ph— 7-SO₂CH₃ 11 iso-propyl Ph— 7-SCH₂CH₃ 12iso-propyl Ph— 7-NH₂ 13 iso-propyl Ph— 7-NHOH 14 iso-propyl Ph— 7-NHCH₃15 iso-propyl Ph— 7-N(CH₃)₂ 16 iso-propyl Ph— 7-N⁺(CH₃)₃, I⁻ 17iso-propyl Ph— 7-NHC(═O)CH₃ 18 iso-propyl Ph— 7-N(CH₂CH₃)₂ 19 iso-propylPh— 7-NMeCH₂CO₂H 20 iso-propyl Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 iso-propylPh— 7-(N)-morpholine 22 iso-propyl Ph— 7-(N)-azetidine 23 iso-propyl Ph—7-(N)—N-methylazetidinium, I⁻ 24 iso-propyl Ph— 7-(N)-pyrrolidine 25iso-propyl Ph— 7-(N)—N-methyl-pyrrolidinium, I⁻ 26 iso-propyl Ph—7-(N)—N-methyl-morpholinium, I⁻ 27 iso-propyl Ph—7-(N)—N′-methylpiperazine 28 iso-propyl Ph—7-(N)—N′-dimethylpiperazinium, I⁻ 29 iso-propyl Ph— 7-NH—CBZ 30iso-propyl Ph— 7-NHC(O)C₅H₁₁ 31 iso-propyl Ph— 7-NHC(O)CH₂Br 32iso-propyl Ph— 7-NH—C(NH)NH₂ 33 iso-propyl Ph— 7-(2)-thiophene 34iso-propyl Ph— 8-methyl 35 iso-propyl Ph— 8-ethyl 36 iso-propyl Ph—8-iso-propyl 37 iso-propyl Ph— 8-tert-butyl 38 iso-propyl Ph— 8-OH 39iso-propyl Ph— 8-OCH₃ 40 iso-propyl Ph— 8-O(iso-propyl) 41 iso-propylPh— 8-SCH₃ 42 iso-propyl Ph— 8-SOCH₃ 43 iso-propyl Ph— 8-SO₂CH₃ 44iso-propyl Ph— 8-SCH₂CH₃ 45 iso-propyl Ph— 8-NH₂ 46 iso-propyl Ph—8-NHOH 47 iso-propyl Ph— 8-NHCH₃ 48 iso-propyl Ph— 8-N(CH₃)₂ 49iso-propyl Ph— 8-N⁺(CH₃)₃, I⁻ 50 iso-propyl Ph— 8-NHC(═O)CH₃ 51iso-propyl Ph— 8-N(CH₂CH₃)₂ 52 iso-propyl Ph— 8-NMeCH₂CO₂H 53 iso-propylPh— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 iso-propyl Ph— 8-(N)-morpholine 55iso-propyl Ph— 8-(N)-azetidine 56 iso-propyl Ph—8-(N)—N-methylazetidinium, I⁻ 57 iso-propyl Ph— 8-(N)-pyrrolidine 58iso-propyl Ph— 8-(N)—N-methyl-pyrrolidinium, I⁻ 59 iso-propyl Ph—8-(N)—N-methyl-morpholinium, I⁻ 60 iso-propyl Ph—8-(N)—N′methylpiperazine 61 iso-propyl Ph—8-(N)—N′-dimethylpiperazinium, I⁻ 62 iso-propyl Ph— 8-NH—CBZ 63iso-propyl Ph— 8-NHC(O)C₅H₁₁ 64 iso-propyl Ph— 8-NHC(O)CH₂Br 65iso-propyl Ph— 8-NH—C(NH)NH₂ 66 iso-propyl Ph— 8-(2)-thiophene 67iso-propyl Ph— 9-methyl 68 iso-propyl Ph— 9-ethyl 69 iso-propyl Ph—9-iso-propyl 70 iso-propyl Ph— 9-tert-butyl 71 iso-propyl Ph— 9-OH 72iso-propyl Ph— 9-OCH₃ 73 iso-propyl Ph— 9-O(iso-propyl) 74 iso-propylPh— 9-SCH₃ 75 iso-propyl Ph— 9-SOCH₃ 76 iso-propyl Ph— 9-SO₂CH₃ 77iso-propyl Ph— 9-SCH₂CH₃ 78 iso-propyl Ph— 9-NH₂ 79 iso-propyl Ph—9-NHOH 80 iso-propyl Ph— 9-NHCH₃ 81 iso-propyl Ph— 9-N(CH₃)₂ 82iso-propyl Ph— 9-N⁺(CH₃)₃, I⁻ 83 iso-propyl Ph— 9-NHC(═O)CH₃ 84iso-propyl Ph— 9-N(CH₂CH₃)₂ 85 iso-propyl Ph— 9-NMeCH₂CO₂H 86 iso-propylPh— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 iso-propyl Ph— 9-(N)-morpholine 88iso-propyl Ph— 9-(N)-azetidine 89 iso-propyl Ph—9-(N)—N-methylazetidinium, I⁻ 90 iso-propyl Ph— 9-(N)-pyrrolidine 91iso-propyl Ph— 9-(N)—N-methyl-pyrrolidinium, I⁻ 92 iso-propyl Ph—9-(N)—N-methyl-morpholinium, I⁻ 93 iso-propyl Ph—9-(N)—N′-methylpiperazine 93 iso-propyl Ph—9-(N)—N′-dimethylpiperazinium, I⁻ 95 iso-propyl Ph— 9-NH—CBZ 96iso-propyl Ph— 9-NHC(O)C₅H₁₁ 97 iso-propyl Ph— 9-NHC(O)CH₂Br 98iso-propyl Ph— 9-NH—C(NH)NH₂ 99 iso-propyl Ph— 9-(2)-thiophene 100iso-propyl Ph— 7-OCH₃, 8-OCH₃ 101 iso-propyl Ph— 7-SCH₃, 8-OCH₃ 102iso-propyl Ph— 7-SCH₃, 8-SCH₃ 103 iso-propyl Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃F101.007 01 iso-butyl Ph— 7-methyl 02 iso-butyl Ph— 7-ethyl 03 iso-butylPh— 7-iso-propyl 04 iso-butyl Ph— 7-tert-butyl 05 iso-butyl Ph— 7-OH 06iso-butyl Ph— 7-OCH₃ 07 iso-butyl Ph— 7-O(iso-propyl) 08 iso-butyl Ph—7-SCH₃ 09 iso-butyl Ph— 7-SOCH₃ 10 iso-butyl Ph— 7-SO₂CH₃ 11 iso-butylPh— 7-SCH₂CH₃ 12 iso-butyl Ph— 7-NH₂ 13 iso-butyl Ph— 7-NHOH 14iso-butyl Ph— 7-NHCH₃ 15 iso-butyl Ph— 7-N(CH₃)₂ 16 iso-butyl Ph—7-N⁺(CH₃)₃, I⁻ 17 iso-butyl Ph— 7-NHC(═O)CH₃ 18 iso-butyl Ph—7-N(CH₂CH₃)₂ 19 iso-butyl Ph— 7-NMeCH₂CO₂H 20 iso-butyl Ph—7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 iso-butyl Ph— 7-(N)-morpholine 22 iso-butyl Ph—7-(N)-azetidine 23 iso-butyl Ph— 7-(N)—N-methylazetidinium, I⁻ 24iso-butyl Ph— 7-(N)-pyrrolidine 25 iso-butyl Ph—7-(N)—N-methyl-pyrrolidinium, I⁻ 26 iso-butyl Ph—7-(N)—N-methyl-morpholinium, I⁻ 27 iso-butyl Ph—7-(N)—N′-methylpiperazine 28 iso-butyl Ph—7-(N)—N′-dimethylpiperazinium, I⁻ 29 iso-butyl Ph— 7-NH—CBZ 30 iso-butylPh— 7-NHC(O)C₅H₁₁ 31 iso-butyl Ph— 7-NHC(O)CH₂Br 32 iso-butyl Ph—7-NH—C(NH)NH₂ 33 iso-butyl Ph— 7-(2)-thiophene 34 iso-butyl Ph— 8-methyl35 iso-butyl Ph— 8-ethyl 36 iso-butyl Ph— 8-iso-propyl 37 iso-butyl Ph—8-tert-butyl 38 iso-butyl Ph— 8-OH 39 iso-butyl Ph— 8-OCH₃ 40 iso-butylPh— 8-O(iso-propyl) 41 iso-butyl Ph— 8-SCH₃ 42 iso-butyl Ph— 8-SOCH₃ 43iso-butyl Ph— 8-SO₂CH₃ 44 iso-butyl Ph— 8-SCH₂CH₃ 45 iso-butyl Ph— 8-NH₂46 iso-butyl Ph— 8-NHOH 47 iso-butyl Ph— 8-NHCH₃ 48 iso-butyl Ph—8-N(CH₃)₂ 49 iso-butyl Ph— 8-N⁺(CH₃)₃, I⁻ 50 iso-butyl Ph— 8-NHC(═O)CH₃51 iso-butyl Ph— 8-N(CH₂CH₃)₂ 52 iso-butyl Ph— 8-NMeCH₂CO₂H 53 iso-butylPh— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 iso-butyl Ph— 8-(N)-morpholine 55 iso-butylPh— 8-(N)-azetidine 56 iso-butyl Ph— 8-(N)—N-methylazetidinium, I⁻ 57iso-butyl Ph— 8-(N)-pyrrolidine 58 iso-butyl Ph—8-(N)—N-methyl-pyrrolidinium, I⁻ 59 iso-butyl Ph—8-(N)—N-methyl-morpholinium, I⁻ 60 iso-butyl Ph—8-(N)—N′-methylpiperazine 61 iso-butyl Ph—8-(N)—N′-dimethylpiperazinium, I⁻ 62 iso-butyl Ph— 8-NH—CBZ 63 iso-butylPh— 8-NHC(O)C₅H₁₁ 64 iso-butyl Ph— 8-NHC(O)CH₂Br 65 iso-butyl Ph—8-NH—C(NH)NH₂ 66 iso-butyl Ph— 8-(2)-thiophene 67 iso-butyl Ph— 9-methyl68 iso-butyl Ph— 9-ethyl 69 iso-butyl Ph— 9-iso-propyl 70 iso-butyl Ph—9-tert-butyl 71 iso-butyl Ph— 9-OH 72 iso-butyl Ph— 9-OCH₃ 73 iso-butylPh— 9-O(iso-propyl) 74 iso-butyl Ph— 9-SCH₃ 75 iso-butyl Ph— 9-SOCH₃ 76iso-butyl Ph— 9-SO₂CH₃ 77 iso-butyl Ph— 9-SCH₂CH₃ 78 iso-butyl Ph— 9-NH₂79 iso-butyl Ph— 9-NHOH 80 iso-butyl Ph— 9-NHCH₃ 81 iso-butyl Ph—9-N(CH₃)₂ 82 iso-butyl Ph— 9-N⁺(CH₃)₃, I⁻ 83 iso-butyl Ph— 9-NHC(═O)CH₃84 iso-butyl Ph— 9-N(CH₂CH₃)₂ 85 iso-butyl Ph— 9-NMeCH₂CO₂H 86 iso-butylPh— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 iso-butyl Ph— 9-(N)-morpholine 88 iso-butylPh— 9-(N)-azetidine 89 iso-butyl Ph— 9-(N)—N-methylazetidinium, I⁻ 90iso-butyl Ph— 9-(N)-pyrrolidine 91 iso-butyl Ph—9-(N)—N-methyl-pyrrolidinium, I⁻ 92 iso-butyl Ph—9-(N)—N-methyl-morpholinium, I⁻ 93 iso-butyl Ph—9-(N)—N′-methylpiperazine 93 iso-butyl Ph—9-(N)—N′-dimethylpiperazinium, I⁻ 95 iso-butyl Ph— 9-NH—CBZ 96 iso-butylPh— 9-NHC(O)C₅H₁₁ 97 iso-butyl Ph— 9-NHC(O)CH₂Br 98 iso-butyl Ph—9-NH—C(NH)NH₂ 99 iso-butyl Ph— 9-(2)-thiophene 100 iso-butyl Ph— 7-OCH₃,8-OCH₃ 101 iso-butyl Ph— 7-SCH₃, 8-OCH₃ 102 iso-butyl Ph— 7-SCH₃, 8-SCH₃103 iso-butyl Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃ F101.008 01 iso-pentyl Ph—7-methyl 02 iso-pentyl Ph— 7-ethyl 03 iso-pentyl Ph— 7-iso-propyl 04iso-pentyl Ph— 7-tert-butyl 05 iso-pentyl Ph— 7-OH 06 iso-pentyl Ph—7-OCH₃ 07 iso-pentyl Ph— 7-O(iso-propyl) 08 iso-pentyl Ph— 7-SCH₃ 09iso-pentyl Ph— 7-SOCH₃ 10 iso-pentyl Ph— 7-SO₂CH₃ 11 iso-pentyl Ph—7-SCH₂CH₃ 12 iso-pentyl Ph— 7-NH₂ 13 iso-pentyl Ph— 7-NHOH 14 iso-pentylPh— 7-NHCH₃ 15 iso-pentyl Ph— 7-N(CH₃)₂ 16 iso-pentyl Ph— 7-N⁺(CH₃)₃, I⁻17 iso-pentyl Ph— 7-NHC(═O)CH₃ 18 iso-pentyl Ph— 7-N(CH₂CH₃)₂ 19iso-pentyl Ph— 7-NMeCH₂CO₂H 20 iso-pentyl Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21iso-pentyl Ph— 7-(N)-morpholine 22 iso-pentyl Ph— 7-(N)-azetidine 23iso-pentyl Ph— 7-(N)—N-methylazetidinium, I⁻ 24 iso-pentyl Ph—7-(N)-pyrrolidine 25 iso-pentyl Ph— 7-(N)—N-methyl-pyrrolidinium, I⁻ 26iso-pentyl Ph— 7-(N)—N-methyl-morpholinium, I⁻ 27 iso-pentyl Ph—7-(N)—N′-methylpiperazine 28 iso-pentyl Ph—7-(N)—N′-dimethylpiperazinium, I⁻ 29 iso-pentyl Ph— 7-NH—CBZ 30iso-pentyl Ph— 7-NHC(O)C₅H₁₁ 31 iso-pentyl Ph— 7-NHC(O)CH₂Br 32iso-pentyl Ph— 7-NH—C(NH)NH₂ 33 iso-pentyl Ph— 7-(2)-thiophene 34iso-pentyl Ph— 8-methyl 35 iso-pentyl Ph— 8-ethyl 36 iso-pentyl Ph—8-iso-propyl 37 iso-pentyl Ph— 8-tert-butyl 38 iso-pentyl Ph— 8-OH 39iso-pentyl Ph— 8-OCH₃ 40 iso-pentyl Ph— 8-O(iso-propyl) 41 iso-pentylPh— 8-SCH₃ 42 iso-pentyl Ph— 8-SOCH₃ 43 iso-pentyl Ph— 8-SO₂CH₃ 44iso-pentyl Ph— 8-SCH₂CH₃ 45 iso-pentyl Ph— 8-NH₂ 46 iso-pentyl Ph—8-NHOH 47 iso-pentyl Ph— 8-NHCH₃ 48 iso-pentyl Ph— 8-N(CH₃)₂ 49iso-pentyl Ph— 8-N⁺(CH₃)₃, I⁻ 50 iso-pentyl Ph— 8-NHC(═O)CH₃ 51iso-pentyl Ph— 8-N(CH₂CH₃)₂ 52 iso-pentyl Ph— 8-NMeCH₂CO₂H 53 iso-pentylPh— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 iso-pentyl Ph— 8-(N)-morpholine 55iso-pentyl Ph— 8-(N)-azetidine 56 iso-pentyl Ph—8-(N)—N-methylazetidinium, I⁻ 57 iso-pentyl Ph— 8-(N)-pyrrolidine 58iso-pentyl Ph— 8-(N)—N-methyl-pyrrolidinium, I⁻ 59 iso-pentyl Ph—8-(N)—N-methyl-morpholinium, I⁻ 60 iso-pentyl Ph—8-(N)—N′-methylpiperazine 61 iso-pentyl Ph—8-(N)—N′-dimethylpiperazinium, I⁻ 62 iso-pentyl Ph— 8-NH—CBZ 63iso-pentyl Ph— 8-NHC(O)C₅H₁₁ 64 iso-pentyl Ph— 8-NHC(O)CH₂Br 65iso-pentyl Ph— 8-NH—C(NH)NH₂ 66 iso-pentyl Ph— 8-(2)-thiophene 67iso-pentyl Ph— 9-methyl 68 iso-pentyl Ph— 9-ethyl 69 iso-pentyl Ph—9-iso-propyl 70 iso-pentyl Ph— 9-tert-butyl 71 iso-pentyl Ph— 9-OH 72iso-pentyl Ph— 9-OCH₃ 73 iso-pentyl Ph— 9-O(iso-propyl) 74 iso-pentylPh— 9-SCH₃ 75 iso-pentyl Ph— 9-SOCH₃ 76 iso-pentyl Ph— 9-SO₂CH₃ 77iso-pentyl Ph— 9-SCH₂CH₃ 78 iso-pentyl Ph— 9-NH₂ 79 iso-pentyl Ph—9-NHOH 80 iso-pentyl Ph— 9-NHCH₃ 81 iso-pentyl Ph— 9-N(CH₃)₂ 82iso-pentyl Ph— 9-N⁺(CH₃)₃, I⁻ 83 iso-pentyl Ph— 9-NHC(═O)CH₃ 84iso-pentyl Ph— 9-N(CH₂CH₃)₂ 85 iso-pentyl Ph— 9-NMeCH₂CO₂H 86 iso-pentylPh— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 iso-pentyl Ph— 9-(N)-morpholine 88iso-pentyl Ph— 9-(N)-azetidine 89 iso-pentyl Ph—9-(N)—N-methylazetidinium, I⁻ 90 iso-pentyl Ph— 9-(N)-pyrrolidine 91iso-pentyl Ph— 9-(N)—N-methyl-pyrrolidinium, I⁻ 92 iso-pentyl Ph—9-(N)—N-methyl-morpholinium, I⁻ 93 iso-pentyl Ph—9-(N)—N′-methylpiperazine 93 iso-pentyl Ph—9-(N)—N′-dimethylpiperazinium, I⁻ 95 iso-pentyl Ph— 9-NH—CBZ 96iso-pentyl Ph— 9-NHC(O)C₅H₁₁ 97 iso-pentyl Ph— 9-NHC(O)CH₂Br 98iso-pentyl Ph— 9-NH—C(NH)NH₂ 99 iso-pentyl Ph— 9-(2)-thiophene 100iso-pentyl Ph— 7-OCH₃, 8-OCH₃ 101 iso-pentyl Ph— 7-SCH₃, 8-OCH₃ 102iso-pentyl Ph— 7-SCH₃, 8-SCH₃ 103 iso-pentyl Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃F101.009 01 CH₂C(═O)C₂H₅ Ph— 7-methyl 02 CH₂C(═O)C₂H₅ Ph— 7-ethyl 03CH₂C(═O)C₂H₅ Ph— 7-iso-propyl 04 CH₂C(═O)C₂H₅ Ph— 7-tert-butyl 05CH₂C(═O)C₂H₅ Ph— 7-OH 06 CH₂C(═O)C₂H₅ Ph— 7-OCH₃ 07 CH₂C(═O)C₂H₅ Ph—7-O(iso-propyl) 08 CH₂C(═O)C₂H₅ Ph— 7-SCH₃ 09 CH₂C(═O)C₂H₅ Ph— 7-SOCH₃10 CH₂C(═O)C₂H₅ Ph— 7-SO₂CH₃ 11 CH₂C(═O)C₂H₅ Ph— 7-SCH₂CH₃ 12CH₂C(═O)C₂H₅ Ph— 7-NH₂ 13 CH₂C(═O)C₂H₅ Ph— 7-NHOH 14 CH₂C(═O)C₂H₅ Ph—7-NHCH₃ 15 CH₂C(═O)C₂H₅ Ph— 7-N(CH₃)₂ 16 CH₂C(═O)C₂H₅ Ph— 7-N⁺(CH₃)₃, I⁻17 CH₂C(═O)C₂H₅ Ph— 7-NHC(═O)CH₃ 18 CH₂C(═O)C₂H₅ Ph— 7-N(CH₂CH₃)₂ 19CH₂C(═O)C₂H₅ Ph— 7-NMeCH₂CO₂H 20 CH₂C(═O)C₂H₅ Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻21 CH₂C(═O)C₂H₅ Ph— 7-(N)-morpholine 22 CH₂C(═O)C₂H₅ Ph— 7-(N)-azetidine23 CH₂C(═O)C₂H₅ Ph— 7-(N)—N-methylazetidinium, I⁻ 24 CH₂C(═O)C₂H₅ Ph—7-(N)-pyrrolidine 25 CH₂C(═O)C₂H₅ Ph— 7-(N)—N-methyl-pyrrolidinium, I⁻26 CH₂C(═O)C₂H₅ Ph— 7-(N)—N-methyl-morpholinium, I⁻ 27 CH₂C(═O)C₂H₅ Ph—7-(N)—N′-methylpiperazine 28 CH₂C(═O)C₂H₅ Ph—7-(N)—N′-dimethylpiperazinium, I⁻ 29 CH₂C(═O)C₂H₅ Ph— 7-NH—CBZ 30CH₂C(═O)C₂H₅ Ph— 7-NHC(O)C₅H₁₁ 31 CH₂C(═O)C₂H₅ Ph— 7-NHC(O)CH₂Br 32CH₂C(═O)C₂H₅ Ph— 7-NH—C(NH)NH₂ 33 CH₂C(═O)C₂H₅ Ph— 7-(2)-thiophene 34CH₂C(═O)C₂H₅ Ph— 8-methyl 35 CH₂C(═O)C₂H₅ Ph— 8-ethyl 36 CH₂C(═O)C₂H₅Ph— 8-iso-propyl 37 CH₂C(═O)C₂H₅ Ph— 8-tert-butyl 38 CH₂C(═O)C₂H₅ Ph—8-OH 39 CH₂C(═O)C₂H₅ Ph— 8-OCH₃ 40 CH₂C(═O)C₂H₅ Ph— 8-O(iso-propyl) 41CH₂C(═O)C₂H₅ Ph— 8-SCH₃ 42 CH₂C(═O)C₂H₅ Ph— 8-SOCH₃ 43 CH₂C(═O)C₂H₅ Ph—8-SO₂CH₃ 44 CH₂C(═O)C₂H₅ Ph— 8-SCH₂CH₃ 45 CH₂C(═O)C₂H₅ Ph— 8-NH₂ 46CH₂C(═O)C₂H₅ Ph— 8-NHOH 47 CH₂C(═O)C₂H₅ Ph— 8-NHCH₃ 48 CH₂C(═O)C₂H₅ Ph—8-N(CH₃)₂ 49 CH₂C(═O)C₂H₅ Ph— 8-N⁺(CH₃)₃, I⁻ 50 CH₂C(═O)C₂H₅ Ph—8-NHC(═O)CH₃ 51 CH₂C(═O)C₂H₅ Ph— 8-N(CH₂CH₃)₂ 52 CH₂C(═O)C₂H₅ Ph—8-NMeCH₂CO₂H 53 CH₂C(═O)C₂H₅ Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 CH₂C(═O)C₂H₅Ph— 8-(N)-morpholine 55 CH₂C(═O)C₂H₅ Ph— 8-(N)-azetidine 56 CH₂C(═O)C₂H₅Ph— 8-(N)—N-methylazetidinium, I⁻ 57 CH₂C(═O)C₂H₅ Ph— 8-(N)-pyrrolidine58 CH₂C(═O)C₂H₅ Ph— 8-(N)—N-methyl-pyrrolidinium, I⁻ 59 CH₂C(═O)C₂H₅ Ph—8-(N)—N-methyl-morpholinium, I⁻ 60 CH₂C(═O)C₂H₅ Ph—8-(N)—N′-methylpiperazine 61 CH₂C(═O)C₂H₅ Ph—8-(N)—N′-dimethylpiperazinium, I⁻ 62 CH₂C(═O)C₂H₅ Ph— 8-NH—CBZ 63CH₂C(═O)C₂H₅ Ph— 8-NHC(O)C₅H₁₁ 64 CH₂C(═O)C₂H₅ Ph— 8-NHC(O)CH₂Br 65CH₂C(═O)C₂H₅ Ph— 8-NH—C(NH)NH₂ 66 CH₂C(═O)C₂H₅ Ph— 8-(2)-thiophene 67CH₂C(═O)C₂H₅ Ph— 9-methyl 68 CH₂C(═O)C₂H₅ Ph— 9-ethyl 69 CH₂C(═O)C₂H₅Ph— 9-iso-propyl 70 CH₂C(═O)C₂H₅ Ph— 9-tert-butyl 71 CH₂C(═O)C₂H₅ Ph—9-OH 72 CH₂C(═O)C₂H₅ Ph— 9-OCH₃ 73 CH₂C(═O)C₂H₅ Ph— 9-O(iso-propyl) 74CH₂C(═O)C₂H₅ Ph— 9-SCH₃ 75 CH₂C(═O)C₂H₅ Ph— 9-SOCH₃ 76 CH₂C(═O)C₂H₅ Ph—9-SO₂CH₃ 77 CH₂C(═O)C₂H₅ Ph— 9-SCH₂CH₃ 78 CH₂C(═O)C₂H₅ Ph— 9-NH₂ 79CH₂C(═O)C₂H₅ Ph— 9-NHOH 80 CH₂C(═O)C₂H₅ Ph— 9-NHCH₃ 81 CH₂C(═O)C₂H₅ Ph—9-N(CH₃)₂ 82 CH₂C(═O)C₂H₅ Ph— 9-N⁺(CH₃)₃, I⁻ 83 CH₂C(═O)C₂H₅ Ph—9-NHC(═O)CH₃ 84 CH₂C(═O)C₂H₅ Ph— 9-N(CH₂CH₃)₂ 85 CH₂C(═O)C₂H₅ Ph—9-NMeCH₂CO₂H 86 CH₂C(═O)C₂H₅ Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 CH₂C(═O)C₂H₅Ph— 9-(N)-morpholine 88 CH₂C(═O)C₂H₅ Ph— 9-(N)-azetidine 89 CH₂C(═O)C₂H₅Ph— 9-(N)—N-methylazetidinium, I⁻ 90 CH₂C(═O)C₂H₅ Ph— 9-(N)-pyrrolidine91 CH₂C(═O)C₂H₅ Ph— 9-(N)—N-methyl-pyrrolidinium, I⁻ 92 CH₂C(═O)C₂H₅ Ph—9-(N)—N-methyl-morpholinium, I⁻ 93 CH₂C(═O)C₂H₅ Ph—9-(N)—N′-methylpiperazine 93 CH₂C(═O)C₂H₅ Ph—9-(N)—N′-dimethylpiperazinium, I⁻ 95 CH₂C(═O)C₂H₅ Ph— 9-NH—CBZ 96CH₂C(═O)C₂H₅ Ph— 9-NHC(O)C₅H₁₁ 97 CH₂C(═O)C₂H₅ Ph— 9-NHC(O)CH₂Br 98CH₂C(═O)C₂H₅ Ph— 9-NH—C(NH)NH₂ 99 CH₂C(═O)C₂H₅ Ph— 9-(2)-thiophene 100CH₂C(═O)C₂H₅ Ph— 7-OCH₃, 8-OCH₃ 101 CH₂C(═O)C₂H₅ Ph— 7-SCH₃, 8-OCH₃ 102CH₂C(═O)C₂H₅ Ph— 7-SCH₃, 8-SCH₃ 103 CH₂C(═O)C₂H₅ Ph— 6-OCH₃, 7-OCH₃,8-OCH₃ F101.010 01 CH₂OC₂H₅ Ph— 7-methyl 02 CH₂OC₂H₅ Ph— 7-ethyl 03CH₂OC₂H₅ Ph— 7-iso-propyl 04 CH₂OC₂H₅ Ph— 7-tert-butyl 05 CH₂OC₂H₅ Ph—7-OH 06 CH₂OC₂H₅ Ph— 7-OCH₃ 07 CH₂OC₂H₅ Ph— 7-O(iso-propyl) 08 CH₂OC₂H₅Ph— 7-SCH₃ 09 CH₂OC₂H₅ Ph— 7-SOCH₃ 10 CH₂OC₂H₅ Ph— 7-SO₂CH₃ 11 CH₂OC₂H₅Ph— 7-SCH₂CH₃ 12 CH₂OC₂H₅ Ph— 7-NH₂ 13 CH₂OC₂H₅ Ph— 7-NHOH 14 CH₂OC₂H₅Ph— 7-NHCH₃ 15 CH₂OC₂H₅ Ph— 7-N(CH₃)₂ 16 CH₂OC₂H₅ Ph— 7-N⁺(CH₃)₃, I⁻ 17CH₂OC₂H₅ Ph— 7-NHC(═O)CH₃ 18 CH₂OC₂H₅ Ph— 7-N(CH₂CH₃)₂ 19 CH₂OC₂H₅ Ph—7-NMeCH₂CO₂H 20 CH₂OC₂H₅ Ph— 7-N⁺(Me)₂CH₂CO₂H I⁻ 21 CH₂OC₂H₅ Ph—7-(N)-morpholine 22 CH₂OC₂H₅ Ph— 7-(N)-azetidine 23 CH₂OC₂H₅ Ph—7-(N)—N-methylazetidinium, I⁻ 24 CH₂OC₂H₅ Ph— 7-(N)-pyrrolidine 25CH₂OC₂H₅ Ph— 7-(N)—N-methyl-pyrrolidinium, I⁻ 26 CH₂OC₂H₅ Ph—7-(N)—N-methyl-morpholinium, I⁻ 27 CH₂OC₂H₅ Ph—7-(N)—N′-methylpiperazine 28 CH₂OC₂H₅ Ph— 7-(N)—N′-dimethylpiperazinium,I⁻ 29 CH₂OC₂H₅ Ph— 7-NH—CBZ 30 CH₂OC₂H₅ Ph— 7-NHC(O)C₅H₁₁ 31 CH₂OC₂H₅Ph— 7-NHC(O)CH₂Br 32 CH₂OC₂H₅ Ph— 7-NH—C(NH)NH₂ 33 CH₂OC₂H₅ Ph—7-(2)-thiophene 34 CH₂OC₂H₅ Ph— 8-methyl 35 CH₂OC₂H₅ Ph— 8-ethyl 36CH₂OC₂H₅ Ph— 8-iso-propyl 37 CH₂OC₂H₅ Ph— 8-tert-butyl 38 CH₂OC₂H₅ Ph—8-OH 39 CH₂OC₂H₅ Ph— 8-OCH₃ 40 CH₂OC₂H₅ Ph— 8-O(iso-propyl) 41 CH₂OC₂H₅Ph— 8-SCH₃ 42 CH₂OC₂H₅ Ph— 8-SOCH₃ 43 CH₂OC₂H₅ Ph— 8-SO₂CH₃ 44 CH₂OC₂H₅Ph— 8-SCH₂CH₃ 45 CH₂OC₂H₅ Ph— 8-NH₂ 46 CH₂OC₂H₅ Ph— 8-NHOH 47 CH₂OC₂H₅Ph— 8-NHOH₃ 48 CH₂OC₂H₅ Ph— 8-N(CH₃)₂ 49 CH₂OC₂H₅ Ph— 8-N⁺(CH₃)₃, I⁻ 50CH₂OC₂H₅ Ph— 8-NHC(═O)CH₃ 51 CH₂OC₂H₅ Ph— 8-N(CH₂CH₃)₂ 52 CH₂OC₂H₅ Ph—8-NMeCH₂CO₂H 53 CH₂OC₂H₅ Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54 CH₂OC₂H₅ Ph—8-(N)-morpholine 55 CH₂OC₂H₅ Ph— 8-(N)-azetidine 56 CH₂OC₂H₅ Ph—8-(N)—N-methylazetidinium, I⁻ 57 CH₂OC₂H₅ Ph— 8-(N)-pyrrolidine 58CH₂OC₂H₅ Ph— 8-(N)—N-methyl-pyrrolidine, I⁻ 59 CH₂OC₂H₅ Ph—8-(N)—N-methyl-morpholinium, I⁻ 60 CH₂OC₂H₅ Ph—8-(N)—N′-methylpiperazine 61 CH₂OC₂H₅ Ph— 8-(N)—N′-dimethylpiperazinium,I⁻ 62 CH₂OC₂H₅ Ph— 8-NH—CBZ 63 CH₂OC₂H₅ Ph— 8-NHC(O)C₅H₁₁ 64 CH₂OC₂H₅Ph— 8-NHC(O)CH₂Br 65 CH₂OC₂H₅ Ph— 8-NH—C(NH)NH₂ 66 CH₂OC₂H₅ Ph—8-(2)-thiophene 67 CH₂OC₂H₅ Ph— 9-methyl 68 CH₂OC₂H₅ Ph— 9-ethyl 69CH₂OC₂H₅ Ph— 9-iso-propyl 70 CH₂OC₂H₅ Ph— 9-tert-butyl 71 CH₂OC₂H₅ Ph—9-OH 72 CH₂OC₂H₅ Ph— 9-OCH₃ 73 CH₂OC₂H₅ Ph— 9-O(iso-propyl) 74 CH₂OC₂H₅Ph— 9-SCH₃ 75 CH₂OC₂H₅ Ph— 9-SOCH₃ 76 CH₂OC₂H₅ Ph— 9-SO₂CH₃ 77 CH₂OC₂H₅Ph— 9-SCH₂CH₃ 78 CH₂OC₂H₅ Ph— 9-NH₂ 79 CH₂OC₂H₅ Ph— 9-NHOH 80 CH₂OC₂H₅Ph— 9-NHCH₃ 81 CH₂OC₂H₅ Ph— 9-N(CH₃)₂ 82 CH₂OC₂H₅ Ph— 9-N⁺(CH₃)₃, I⁻ 83CH₂OC₂H₅ Ph— 9-NHC(═O)CH₃ 84 CH₂OC₂H₅ Ph— 9-N(CH₂CH₃)₂ 85 CH₂OC₂H₅ Ph—9-NMeCH₂CO₂H 86 CH₂OC₂H₅ Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87 CH₂OC₂H₅ Ph—9-(N)-morpholine 88 CH₂OC₂H₅ Ph— 9-(N)-azetidine 89 CH₂OC₂H₅ Ph—9-(N)—N-methylazetidinium, I⁻ 90 CH₂OC₂H₅ Ph— 9-(N)-pyrrolidine 91CH₂OC₂H₅ Ph— 9-(N)—N-methyl-pyrrolidine, I⁻ 92 CH₂OC₂H₅ Ph—9-(N)—N-methyl-morpholinium, I⁻ 93 CH₂OC₂H₅ Ph—9-(N)—N′-methylpiperazine 93 CH₂OC₂H₅ Ph— 9-(N)—N′-dimethylpiperazinium,I⁻ 95 CH₂OC₂H₅ Ph— 9-NH—CBZ 96 CH₂OC₂H₅ Ph— 9-NHC(O)C₅H₁₁ 97 CH₂OC₂H₅Ph— 9-NHC(O)CH₂Br 98 CH₂OC₂H₅ Ph— 9-NH—C(NH)NH₂ 99 CH₂OC₂H₅ Ph—9-(2)-thiophene 100 CH₂OC₂H₅ Ph— 7-OCH₃, 8-OCH₃ 101 CH₂OC₂H₅ Ph— 7-SCH₃,8-OCH₃ 102 CH₂OC₂H₅ Ph— 7-SCH₃, 8-SCH₃ 103 CH₂OC₂H₅ Ph— 6-OCH₃, 7-OCH₃,8-OCH₃ F101.011 01 CH₂CH(OH)C₂H₅ Ph— 7-methyl 02 CH₂CH(OH)C₂H₅ Ph—7-ethyl 03 CH₂CH(OH)C₂H₅ Ph— 7-iso-propyl 04 CH₂CH(OH)C₂H₅ Ph—7-tert-butyl 05 CH₂CH(OH)C₂H₅ Ph— 7-OH 06 CH₂CH(OH)C₂H₅ Ph— 7-OCH₃ 07CH₂CH(OH)C₂H₅ Ph— 7-O(iso-propyl) 08 CH₂CH(OH)C₂H₅ Ph— 7-SCH₃ 09CH₂CH(OH)C₂H₅ Ph— 7-SOCH₃ 10 CH₂CH(OH)C₂H₅ Ph— 7-SO₂CH₃ 11 CH₂CH(OH)C₂H₅Ph— 7-SCH₂CH₃ 12 CH₂CH(OH)C₂H₅ Ph— 7-NH₂ 13 CH₂CH(OH)C₂H₅ Ph— 7-NHOH 14CH₂CH(OH)C₂H₅ Ph— 7-NHCH₃ 15 CH₂CH(OH)C₂H₅ Ph— 7-N(CH₃)₂ 16CH₂CH(OH)C₂H₅ Ph— 7-N⁺(CH₃)₃, I⁻ 17 CH₂CH(OH)C₂H₅ Ph— 7-NHC(═O)CH₃ 18CH₂CH(OH)C₂H₅ Ph— 7-N(CH₂CH₃)₂ 19 CH₂CH(OH)C₂H₅ Ph— 7-NMeCH₂CO₂H 20CH₂CH(OH)C₂H₅ Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21 CH₂CH(OH)C₂H₅ Ph—7-(N)-morpholine 22 CH₂CH(OH)C₂H₅ Ph— 7-(N)-azetidine 23 CH₂CH(OH)C₂H₅Ph— 7-(N)—N-methylazetidinium, I⁻ 24 CH₂CH(OH)C₂H₅ Ph— 7-(N)-pyrrolidine25 CH₂CH(OH)C₂H₅ Ph— 7-(N)—N-methyl-pyrrolidinium, I⁻ 26 CH₂CH(OH)C₂H₅Ph— 7-(N)—N-methyl-morpholinium, I⁻ 27 CH₂CH(OH)C₂H₅ Ph—7-(N)—N′-methylpiperazine 28 CH₂CH(OH)C₂H₅ Ph—7-(N)—N′-dimethylpiperazinium, I⁻ 29 CH₂CH(OH)C₂H₅ Ph— 7-NH—CBZ 30CH₂CH(OH)C₂H₅ Ph— 7-NHC(O)C₅H₁₁ 31 CH₂CH(OH)C₂H₅ Ph— 7-NHC(O)CH₂Br 32CH₂CH(OH)C₂H₅ Ph— 7-NH—C(NH)NH₂ 33 CH₂CH(OH)C₂H₅ Ph— 7-(2)-thiophene 34CH₂CH(OH)C₂H₅ Ph— 8-methyl 35 CH₂CH(OH)C₂H₅ Ph— 8-ethyl 36 CH₂CH(OH)C₂H₅Ph— 8-iso-propyl 37 CH₂CH(OH)C₂H₅ Ph— 8-tert-butyl 38 CH₂CH(OH)C₂H₅ Ph—8-OH 39 CH₂CH(OH)C₂H₅ Ph— 8-OCH₃ 40 CH₂CH(OH)C₂H₅ Ph— 8-O(iso-propyl) 41CH₂CH(OH)C₂H₅ Ph— 8-SCH₃ 42 CH₂CH(OH)C₂H₅ Ph— 8-SOCH₃ 43 CH₂CH(OH)C₂H₅Ph— 8-SO₂CH₃ 44 CH₂CH(OH)C₂H₅ Ph— 8-SCH₂CH₃ 45 CH₂CH(OH)C₂H₅ Ph— 8-NH₂46 CH₂CH(OH)C₂H₅ Ph— 8-NHOH 47 CH₂CH(OH)C₂H₅ Ph— 8-NHCH₃ 48CH₂CH(OH)C₂H₅ Ph— 8-N(CH₃)₂ 49 CH₂CH(OH)C₂H₅ Ph— 8-N⁺(CH₃)₃, I⁻ 50CH₂CH(OH)C₂H₅ Ph— 8-NHC(═O)CH₃ 51 CH₂CH(OH)C₂H₅ Ph— 8-N(CH₂CH₃)₂ 52CH₂CH(OH)C₂H₅ Ph— 8-NMeCH₂CO₂H 53 CH₂CH(OH)C₂H₅ Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻54 CH₂CH(OH)C₂H₅ Ph— 8-(N)-morpholine 55 CH₂CH(OH)C₂H₅ Ph—8-(N)-azetidine 56 CH₂CH(OH)C₂H₅ Ph— 8-(N)—N-methylazetidinium, I⁻ 57CH₂CH(OH)C₂H₅ Ph— 8-(N)-pyrrolidine 58 CH₂CH(OH)C₂H₅ Ph—8-(N)—N-methyl-pyrrolidinium, I⁻ 59 CH₂CH(OH)C₂H₅ Ph—8-(N)—N-methyl-morpholinium, I⁻ 60 CH₂CH(OH)C₂H₅ Ph—8-(N)—N′-methylpiperazine 61 CH₂CH(OH)C₂H₅ Ph—8-(N)—N′-dimethylpiperazinium, I⁻ 62 CH₂CH(OH)C₂H₅ Ph— 8-NH—CBZ 63CH₂CH(OH)C₂H₅ Ph— 8-NHC(O)C₅H₁₁ 64 CH₂CH(OH)C₂H₅ Ph— 8-NHC(O)CH₂Br 65CH₂CH(OH)C₂H₅ Ph— 8-NH—C(NH)NH₂ 66 CH₂CH(OH)C₂H₅ Ph— 8-(2)-thiophene 67CH₂CH(OH)C₂H₅ Ph— 9-methyl 68 CH₂CH(OH)C₂H₅ Ph— 9-ethyl 69 CH₂CH(OH)C₂H₅Ph— 9-iso-propyl 70 CH₂CH(OH)C₂H₅ Ph— 9-tert-butyl 71 CH₂CH(OH)C₂H₅ Ph—9-OH 72 CH₂CH(OH)C₂H₅ Ph— 9-OCH₃ 73 CH₂CH(OH)C₂H₅ Ph— 9-O(iso-propyl) 74CH₂CH(OH)C₂H₅ Ph— 9-SCH₃ 75 CH₂CH(OH)C₂H₅ Ph— 9-SOCH₃ 76 CH₂CH(OH)C₂H₅Ph— 9-SO₂CH₃ 77 CH₂CH(OH)C₂H₅ Ph— 9-SCH₂CH₃ 78 CH₂CH(OH)C₂H₅ Ph— 9-NH₂79 CH₂CH(OH)C₂H₅ Ph— 9-NHOH 80 CH₂CH(OH)C₂H₅ Ph— 9-NHCH₃ 81CH₂CH(OH)C₂H₅ Ph— 9-N(CH₃)₂ 82 CH₂CH(OH)C₂H₅ Ph— 9-N⁺(CH₃)₃, I⁻ 83CH₂CH(OH)C₂H₅ Ph— 9-NHC(═O)CH₃ 84 CH₂CH(OH)C₂H₅ Ph— 9-N(CH₂CH₃)₂ 85CH₂CH(OH)C₂H₅ Ph— 9-NMeCH₂CO₂H 86 CH₂CH(OH)C₂H₅ Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻87 CH₂CH(OH)C₂H₅ Ph— 9-(N)-morpholine 88 CH₂CH(OH)C₂H₅ Ph—9-(N)-azetidine 89 CH₂CH(OH)C₂H₅ Ph— 9-(N)—N-methylazetidinium, I⁻ 90CH₂CH(OH)C₂H₅ Ph— 9-(N)-pyrrolidine 91 CH₂CH(OH)C₂H₅ Ph—9-(N)—N-methyl-pyrrolidinium, I⁻ 92 CH₂CH(OH)C₂H₅ Ph—9-(N)—N-methyl-morpholinium, I⁻ 93 CH₂CH(OH)C₂H₅ Ph—9-(N)—N′-methylpiperazine 93 CH₂CH(OH)C₂H₅ Ph—9-(N)—N′-dimethylpiperazinium, I⁻ 95 CH₂CH(OH)C₂H₅ Ph— 9-NH—CBZ 96CH₂CH(OH)C₂H₅ Ph— 9-NHC(O)C₅H₁₁ 97 CH₂CH(OH)C₂H₅ Ph— 9-NHC(O)CH₂Br 98CH₂CH(OH)C₂H₅ Ph— 9-NH—C(NH)NH₂ 99 CH₂CH(OH)C₂H₅ Ph— 9-(2)-thiophene 100CH₂CH(OH)C₂H₅ Ph— 7-OCH₃, 8-OCH₃ 101 CH₂CH(OH)C₂H₅ Ph— 7-SCH₃, 8-OCH₃102 CH₂CH(OH)C₂H₅ Ph— 7-SCH₃, 8-SCH₃ 103 CH₂CH(OH)C₂H₅ Ph— 6-OCH₃,7-OCH₃, 8-OCH₃ F101.012 01 CH₂O-(4-picoline) Ph— 7-methyl 02CH₂O-(4-picoline) Ph— 7-ethyl 03 CH₂O-(4-picoline) Ph— 7-iso-propyl 04CH₂O-(4-picoline) Ph— 7-tert-butyl 05 CH₂O-(4-picoline) Ph— 7-OH 06CH₂O-(4-picoline) Ph— 7-OCH₃ 07 CH₂O-(4-picoline) Ph— 7-O(iso-propyl) 08CH₂O-(4-picoline) Ph— 7-SCH₃ 09 CH₂O-(4-picoline) Ph— 7-SOCH₃ 10CH₂O-(4-picoline) Ph— 7-SO₂CH₃ 11 CH₂O-(4-picoline) Ph— 7-SCH₂CH₃ 12CH₂O-(4-picoline) Ph— 7-NH₂ 13 CH₂O-(4-picoline) Ph— 7-NHOH 14CH₂O-(4-picoline) Ph— 7-NHCH₃ 15 CH₂O-(4-picoline) Ph— 7-N(CH₃)₂ 16CH₂O-(4-picoline) Ph— 7-N⁺(CH₃)₃, I⁻ 17 CH₂O-(4-picoline) Ph—7-NHC(═O)CH₃ 18 CH₂O-(4-picoline) Ph— 7-N(CH₂CH₃)₂ 19 CH₂O-(4-picoline)Ph— 7-NMeCH₂CO₂H 20 CH₂O-(4-picoline) Ph— 7-N⁺(Me)₂CH₂CO₂H, I⁻ 21CH₂O-(4-picoline) Ph— 7-(N)-morpholine 22 CH₂O-(4-picoline) Ph—7-(N)-azetidine 23 CH₂O-(4-picoline) Ph— 7-(N)—N-methylazetidinium, I⁻24 CH₂O-(4-picoline) Ph— 7-(N)-pyrrolidine 25 CH₂O-(4-picoline) Ph—7-(N)—N-methyl-pyrrolidinium, I⁻ 26 CH₂O-(4-picoline) Ph—7-(N)—N-methyl-morpholinium, I⁻ 27 CH₂O-(4-picoline) Ph—7-(N)—N′-methylpiperazine 28 CH₂O-(4-picoline) Ph—7-(N)—N′-dimethylpiperazinium, I⁻ 29 CH₂O-(4-picoline) Ph— 7-NH—CBZ 30CH₂O-(4-picoline) Ph— 7-NHC(O)C₅H₁₁ 31 CH₂O-(4-picoline) Ph—7-NHC(O)CH₂Br 32 CH₂O-(4-picoline) Ph— 7-NH—C(NH)NH₂ 33CH₂O-(4-picoline) Ph— 7-(2)-thiophene 34 CH₂O-(4-picoline) Ph— 8-methyl35 CH₂O-(4-picoline) Ph— 8-ethyl 36 CH₂O-(4-picoline) Ph— 8-iso-propyl37 CH₂O-(4-picoline) Ph— 8-tert-butyl 38 CH₂O-(4-picoline) Ph— 8-OH 39CH₂O-(4-picoline) Ph— 8-OCH₃ 40 CH₂O-(4-picoline) Ph— 8-O(iso-propyl) 41CH₂O-(4-picoline) Ph— 8-SCH₃ 42 CH₂O-(4-picoline) Ph— 8-SOCH₃ 43CH₂O-(4-picoline) Ph— 8-SO₂CH₃ 44 CH₂O-(4-picoline) Ph— 8-SCH₂CH₃ 45CH₂O-(4-picoline) Ph— 8-NH₂ 46 CH₂O-(4-picoline) Ph— 8-NHOH 47CH₂O-(4-picoline) Ph— 8-NHCH₃ 48 CH₂O-(4-picoline) Ph— 8-N(CH₃)₂ 49CH₂O-(4-picoline) Ph— 8-N⁺(CH₃)₃, I⁻ 50 CH₂O-(4-picoline) Ph—8-NHC(═O)CH₃ 51 CH₂O-(4-picoline) Ph— 8-N(CH₂CH₃)₂ 52 CH₂O-(4-picoline)Ph— 8-NMeCH₂CO₂H 53 CH₂O-(4-picoline) Ph— 8-N⁺(Me)₂CH₂CO₂H, I⁻ 54CH₂O-(4-picoline) Ph— 8-(N)-morpholine 55 CH₂O-(4-picoline) Ph—8-(N)-azetidine 56 CH₂O-(4-picoline) Ph— 8-(N)—N-methylazetidinium, I⁻57 CH₂O-(4-picoline) Ph— 8-(N)-pyrrolidine 58 CH₂O-(4-picoline) Ph—8-(N)—N-methyl-pyrrolidinium, I⁻ 59 CH₂O-(4-picoline) Ph—8-(N)—N-methyl-morpholinium, I⁻ 60 CH₂O-(4-picoline) Ph—8-(N)—N′-methylpiperazine 61 CH₂O-(4-picoline) Ph—8-(N)—N′-dimethylpiperazinium, I⁻ 62 CH₂O-(4-picoline) Ph— 8-NH—CBZ 63CH₂O-(4-picoline) Ph— 8-NHC(O)C₅H₁₁ 64 CH₂O-(4-picoline) Ph—8-NHC(O)CH₂Br 65 CH₂O-(4-picoline) Ph— 8-NH—C(NH)NH₂ 66CH₂O-(4-picoline) Ph— 8-(2)-thiophene 67 CH₂O-(4-picoline) Ph— 9-methyl68 CH₂O-(4-picoline) Ph— 9-ethyl 69 CH₂O-(4-picoline) Ph— 9-iso-propyl70 CH₂O-(4-picoline) Ph— 9-tert-butyl 71 CH₂O-(4-picoline) Ph— 9-OH 72CH₂O-(4-picoline) Ph— 9-OCH₃ 73 CH₂O-(4-picoline) Ph— 9-O(iso-propyl) 74CH₂O-(4-picoline) Ph— 9-SCH₃ 75 CH₂O-(4-picoline) Ph— 9-SOCH₃ 76CH₂O-(4-picoline) Ph— 9-SO₂CH₃ 77 CH₂O-(4-picoline) Ph— 9-SCH₂CH₃ 78CH₂O-(4-picoline) Ph— 9-NH₂ 79 CH₂O-(4-picoline) Ph— 9-NHOH 80CH₂O-(4-picoline) Ph— 9-NHCH₃ 81 CH₂O-(4-picoline) Ph— 9-N(CH₃)₂ 82CH₂O-(4-picoline) Ph— 9-N⁺(CH₃)₃, I⁻ 83 CH₂O-(4-picoline) Ph—9-NHC(═O)CH₃ 84 CH₂O-(4-picoline) Ph— 9-N(CH₂CH₃)₂ 85 CH₂O-(4-picoline)Ph— 9-NMeCH₂CO₂H 86 CH₂O-(4-picoline) Ph— 9-N⁺(Me)₂CH₂CO₂H, I⁻ 87CH₂O-(4-picoline) Ph— 9-(N)-morpholine 88 CH₂O-(4-picoline) Ph—9-(N)-azetidine 89 CH₂O-(4-picoline) Ph— 9-(N)—N-methylazetidinium, I⁻90 CH₂O-(4-picoline) Ph— 9-(N)-pyrrolidine 91 CH₂O-(4-picoline) Ph—9-(N)—N-methyl-pyrrolidinium, I⁻ 92 CH₂O-(4-picoline) Ph—9-(N)—N-methylmorpholinium 93 CH₂O-(4-picoline) Ph—9-(N)—N′-methylpiperazine 93 CH₂O-(4-picoline) Ph—9-(N)—N′-dimethylpiperazinium, I⁻ 95 CH₂O-(4-picoline) Ph— 9-NH—CBZ 96CH₂O-(4-picoline) Ph— 9-NHC(O)C₅H₁₁ 97 CH₂O-(4-picoline) Ph—9-NHC(O)CH₂Br 98 CH₂O-(4-picoline) Ph— 9-NH—C(NH)NH₂ 99CH₂O-(4-picoline) Ph— 9-(2)-thiophene 100 CH₂O-(4-picoline) Ph— 7-OCH₃,8-OCH₃ 101 CH₂O-(4-picoline) Ph— 7-SCH₃, 8-OCH₃ 102 CH₂O-(4-picoline)Ph— 7-SCH₃, 8-SCH₃ 103 CH₂O-(4-picoline) Ph— 6-OCH₃, 7-OCH₃, 8-OCH₃

[0226]

Compound Number R¹ R² R³ R⁴ R⁵ 101 ethyl n-butyl OH H phenyl 102 ethyln-butyl OH H phenyl 103 n-butyl ethyl OH H phenyl 104 ethyl n-butyl OH Hphenyl 105 ethyl n-butyl OH H phenyl 106 ethyl n-butyl OH H phenyl 107n-butyl ethyl OH H 4-(decyloxy)phenyl 108 ethyl n-butyl OH H phenyl 109ethyl n-butyl OH H 4-(decyloxy)phenyl 110 ethyl n-butyl OH H phenyl 111n-butyl ethyl OH H 4-hydroxyphenyl 112 ethyl n-butyl OH H

113 ethyl n-butyl OH H 4-hydroxyphenyl 114 ethyl n-butyl OH H4-methoxyphenyl 115 n-butyl ethyl OH H 4-methoxyphenyl 116 ethyl n-butylOH H 4-methoxyphenyl 117 n-butyl ethyl OH H phenyl 118 ethyl n-butyl OHH phenyl 119 ethyl n-butyl OH H phenyl 120 n-butyl ethyl OH H phenyl 121ethyl n-butyl OH H phenyl 122 n-butyl ethyl OH H phenyl 123 ethyln-butyl OH H phenyl 124 n-butyl ethyl OH H phenyl 125 ethyl n-butyl OH Hphenyl 126 n-butyl ethyl OH H 4-fluorophenyl 127 n-butyl ethyl OH H4-fluorophenyl 128 ethyl n-butyl OH H 4-fluorophenyl 129 ethyl n-butylOH H 4-fluorophenyl 131 ethyl n-butyl OH H 4-fluorophenyl 132 ethyln-butyl OH H phenyl 133 ethyl n-butyl OH H phenyl 134 ethyl n-butyl OH Hphenyl 135 ethyl n-butyl OH H phenyl 136 ethyl n-butyl OH H phenyl 137n-butyl ethyl OH H phenyl 138 n-butyl ethyl OH H phenyl 139 n-butylethyl OH H phenyl 140 141 142 ethyl n-butyl H OH H 143 ethyl n-butyl OHH 3-methoxyphenyl 144 ethyl n-butyl OH H 4-fluorophenyl 262 ethyln-butyl OH H 3-methoxyphenyl 263 ethyl n-butyl H OH H 264 ethyl n-butylOH H 3-trifluoromethylphenyl 265 ethyl n-butyl H OH H 266 ethyl n-butylOH H 3-hydroxyphenyl 267 ethyl n-butyl OH H 3-hydroxyphenyl 268 ethyln-butyl OH H 4-fluorophenyl 269 ethyl n-butyl H OH H 270 ethyl n-butylOH H 4-fluorophenyl 271 ethyl n-butyl OH H 3-methoxyphenyl 272 ethyln-butyl H OH H 273 ethyl n-butyl H OH H 274 ethyl n-butyl OH H4-fluorophenyl 275 ethyl n-butyl H OH H 276 ethyl n-butyl OH H3-methoxyphenyl 277 ethyl n-butyl OH H 3-fluorophenyl 278 ethyl n-butylH OH 2-fluorophenyl 279 ethyl n-butyl H OH 3-fluorophenyl 280 ethyln-butyl OH H 2-fluorophenyl 281 ethyl n-butyl OH H 4-fluorophenyl 282ethyl n-butyl OH H 4-fluorophenyl 283 ethyl n-butyl H OH H 284 ethyln-butyl OH H 4-fluorophenyl 286 ethyl ethyl OH H phenyl 287 ethyl ethylOH H phenyl 288 methyl methyl OH H phenyl 289 n-butyl n-butyl OH Hphenyl 290 n-butyl n-butyl OH H phenyl 291 n-butyl n-butyl OH H phenyl292 n-butyl n-butyl OH H 4-fluorophenyl 293 n-butyl n-butyl OH H phenyl294 n-butyl n-butyl OH H phenyl 295 ethyl n-butyl OH H

296 ethyl n-butyl OH H

1000 ethyl n-butyl OH H

1001 ethyl n-butyl OH H

1002 ethyl n-butyl OH H

1003 ethyl n-butyl OH H

1004 ethyl n-butyl OH H

1005 n-butyl n-butyl OH H

1006 n-butyl n-butyl OH H

1007 n-butyl n-butyl OH H

1008 n-butyl n-butyl OH H

1009 n-butyl n-butyl OH H

1010 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl 1011 n-butyl n-butylOH H 3-fluoro-4-(5-triethylammoniumpentyloxy)phenyl, trifluoroacetatesalt 1012 n-butyl n-butyl OH H 4-hydroxyphenyl 1013 n-butyl n-butyl OH H

1014 n-butyl n-butyl OH H 4-methoxyphenyl 1015 n-butyl n-butyl OH H

1016 n-butyl n-butyl OH H

1017 n-butyl n-butyl OH H

1018 n-butyl n-butyl OH H

1019 n-butyl n-butyl OH H

1020 n-butyl n-butyl OH H

1021 n-butyl n-butyl OH H

1022 n-butyl n-butyl OH H

1023 n-butyl n-butyl OH H

1024 n-butyl n-butyl OH H

1025 n-butyl n-butyl OH H

1026 n-butyl n-butyl OH H

1027 n-butyl n-butyl OH H

1028 n-butyl n-butyl OH H

1029 n-butyl n-butyl OH H

1030 n-butyl n-butyl OH H

1031 n-butyl n-butyl OH H

1032 n-butyl n-butyl OH H

1033 n-butyl n-butyl OH H

1034 n-butyl n-butyl OH H

1035 n-butyl n-butyl OH H

1036 n-butyl n-butyl OH H

1037 n-butyl n-butyl OH H 4-hydroxyphenyl 1038 n-butyl n-butyl OH H

1039 n-butyl n-butyl OH H phenyl 1040 n-butyl n-butyl OH H

1041 n-butyl n-butyl OH H

1042 n-butyl n-butyl OH H

1043 n-butyl n-butyl OH H

1044 n-butyl n-butyl OH H

1045 n-butyl n-butyl OH H

1046 n-butyl n-butyl OH H 3-aminophenyl 1047 n-butyl n-butyl OH H

1048 n-butyl n-butyl OH H

1049 n-butyl n-butyl OH H

1050 n-butyl n-butyl OH H

1051 n-butyl n-butyl OH H

1052 n-butyl n-butyl OH H

1053 n-butyl n-butyl OH H

1054 n-butyl n-butyl OH H

1055 n-butyl n-butyl OH H

1056 n-butyl n-butyl OH H

1057 n-butyl n-butyl OH H

1058 n-butyl n-butyl OH H

1059 n-butyl n-butyl OH H

1060 ethyl n-butyl OH H 3-fluoro-4-methoxyphenyl 1061 n-butyl n-butyl OHH

1062 n-butyl n-butyl OH H

1063 n-butyl n-butyl OH H

1064 n-butyl n-butyl OH H

1065 n-butyl n-butyl OH H

1066 n-butyl n-butyl OH H

1067 n-butyl n-butyl OH H thiophen-3-yl 1068 n-butyl n-butyl OH H

1069 n-butyl n-butyl OH H phenyl 1070 n-butyl n-butyl OH H

1071 n-butyl n-butyl OH H

1072 n-butyl n-butyl OH H

1073 n-butyl n-butyl OH H

1074 ethyl n-butyl OH H 3-fluoro-4-methoxyphenyl 1075 n-butyl n-butyl OHH 4-fluorophenyl 1076 n-butyl n-butyl OH H

1077 n-butyl n-butyl OH H 3-hydroxymethylphenyl 1078 ethyl n-butyl OH H4-hydroxyphenyl 1079 ethyl n-butyl OH H

1080 n-butyl n-butyl OH H

1081 n-butyl n-butyl OH H

1082 n-butyl n-butyl OH H 2-pyridyl 1083 n-butyl n-butyl OH H

1084 n-butyl n-butyl OH H

1085 n-butyl n-butyl OH H thiophen-3-yl 1086 n-butyl n-butyl OH H

1087 n-butyl n-butyl OH H

1088 ethyl n-butyl OH H 3,4-methylenedioxyphenyl 1089 ethyl n-butyl OH H4-methyoxyphenyl 1090 n-butyl n-butyl OH H

1091 n-butyl n-butyl OH H

1092 n-butyl n-butyl OH H

1093 n-butyl n-butyl OH H

1094 n-butyl n-butyl OH H

1095 n-butyl n-butyl OH H

1096 n-butyl n-butyl OH H

1097 n-butyl n-butyl OH H

1098 n-butyl n-butyl OH H

1099 ethyl n-butyl OH H 4-methoxyphenyl 1100 n-butyl n-butyl OH H4-methoxyphenyl 1101 n-butyl n-butyl OH H

1102 n-butyl n-butyl OH H 3-carboxymethylphenyl 1103 n-butyl n-butyl OHH

1104 n-butyl n-butyl OH H

1105 n-butyl n-butyl OH H 5-piperonyl 1106 n-butyl n-butyl OH H3-hydroxyphenyl 1107 n-butyl n-butyl OH H

1108 n-butyl n-butyl OH H 3-pyridyl 1109 n-butyl n-butyl OH H

1110 n-butyl n-butyl OH H

1111 n-butyl n-butyl OH H

1112 n-butyl n-butyl OH H 4-pyridyl 1113 n-butyl n-butyl OH H

1114 n-butyl n-butyl OH H 3-methoxyphenyl 1115 n-butyl n-butyl OH H4-fluorophenyl 1116 ethyl n-butyl OH H 3-tolyl 1117 ethyl n-butyl OH H

1118 ethyl n-butyl OH H 3-fluoro-4-hydroxyphenyl 1119 n-butyl n-butyl OHH

1120 n-butyl n-butyl OH H

1121 n-butyl n-butyl OH H

1122 n-butyl n-butyl OH H

1123 n-butyl n-butyl OH H phenyl 1124 n-butyl n-butyl OH H3-methoxyphenyl 1125 n-butyl n-butyl OH H 3-chloro-4-methoxyphenyl 1126ethyl n-butyl OH H

1127 n-butyl n-butyl OH H

1128 n-butyl n-butyl OH H 3-fluoro-4-hydroxyphenyl 1129 n-butyl n-butylOH H 4-fluorophenyl 1130 n-butyl n-butyl OH H 3-chloro-4-fluorophenyl1131 ethyl n-butyl OH H 4-methoxyphenyl 1132 n-butyl n-butyl OH H

1133 n-butyl n-butyl OH H 4-cyanomethylphenyl 1134 ethyl n-butyl OH H

1135 n-butyl n-butyl OH H 3,4-dimethoxyphenyl 1136 n-butyl n-butyl OH H

1137 n-butyl n-butyl OH H 4-fluorophenyl 1138 n-butyl n-butyl OH H

1139 n-butyl n-butyl OH H 3,4-difluorophenyl 1140 n-butyl n-butyl OH H3-methoxyphenyl 1141 n-butyl n-butyl OH H 4-fluorophenyl 1142 n-butyln-butyl OH H

1143 n-butyl n-butyl H OH H 1144 n-butyl n-butyl OH H 5-piperonyl 1145n-butyl n-butyl OH H 4-methoxyphenyl 1146 n-butyl n-butyl OH H

1147 n-butyl n-butyl OH H 3-methoxyphenyl 1148 n-butyl n-butyl OH H4-fluorophenyl 1149 n-butyl n-butyl OH H 4-fluorophenyl 1150 n-butyln-butyl OH H 3-methoxyphenyl 1151 n-butyl ethyl OH H3-fluoro-4-methoxyphenyl 1152 n-butyl n-butyl OH H phenyl 1153 n-butyln-butyl OH H 4-fluorophenyl 1154 n-butyl n-butyl OH H 3-methoxyphenyl1155 n-butyl n-butyl OH H 4-fluorophenyl 1156 n-butyl n-butyl OH H4-fluorophenyl 1157 n-butyl n-butyl OH H 4-fluorophenyl 1158 n-butyln-butyl OH H 4-pyridinyl, hydrochloride salt 1159 n-butyl ethyl OH Hphenyl 1160 n-butyl n-butyl OH H 4-fluorophenyl 1161 n-butyl n-butyl OHH 3,5-dichloro-4-methoxyphenyl 1162 n-butyl n-butyl OH H phenyl 1163n-butyl n-butyl OH H 3-(dimethylamino)phenyl 1164 n-butyl n-butyl OH H4-pyridinyl 1165 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl 1166n-butyl n-butyl OH H 3-hydroxyphenyl 1167 n-butyl n-butyl OH H

1168 n-butyl n-butyl OH H 4-hydroxyphenyl 1169 n-butyl n-butyl OH Hphenyl 1170 n-butyl n-butyl OH H 3-methoxyphenyl 1171 n-butyl n-butyl OHH 4-(trifluoromethylsulfonyloxy)phenyl 1172 n-butyl n-butyl OH H4-pyridinyl 1173 n-butyl n-butyl OH H 4-fluorophenyl 1174 ethyl n-butylOH H 3-methoxyphenyl 1175 ethyl n-butyl OH H 3-methoxyphenyl 1176n-butyl n-butyl OH H 4-fluorophenyl 1177 n-butyl n-butyl OH H3-methoxyphenyl 1178 n-butyl n-butyl OH H3-(trifluoromethylsulfonyloxy)phenyl 1179 n-butyl n-butyl OH H phenyl1180 n-butyl n-butyl OH H phenyl 1181 n-butyl n-butyl OH H4-fluorophenyl 1182 n-butyl n-butyl OH H 4-(dimethylamino)phenyl 1183n-butyl n-butyl OH H 3-methoxyphenyl 1184 n-butyl n-butyl OH H4-fluorophenyl 1185 n-butyl n-butyl OH H 4-fluorophenyl 1186 n-butyln-butyl OH H phenyl 1187 n-butyl n-butyl OH H 3-fluorophenyl 1188n-butyl n-butyl OH H 4-methoxyphenyl 1189 n-butyl n-butyl OH H3,4-difluorophenyl 1190 n-butyl n-butyl OH H 2-bromophenyl 1191 n-butyln-butyl OH H 4-(dimethylamino)phenyl 1192 n-butyl n-butyl OH H3-(dimethylamino)phenyl 1193 n-butyl n-butyl OH H4-(2-(2-methylpropyl))phenyl 1194 n-butyl n-butyl OH H

1195 n-butyl n-butyl OH H 4-methoxyphenyl 1196 n-butyl n-butyl OH H

1197 n-butyl ethyl R3 + R3 + phenyl R4 = R4 = oxo oxo 1198 n-butyln-butyl OH H 4-(pyridinyl-N-oxide) 1199 n-butyl n-butyl OH H

1200 n-butyl n-butyl H OH H 1201 n-butyl n-butyl OH H H 1202 n-butyln-butyl OH H

1203 n-butyl n-butyl OH H 5-piperazinyl 1204 n-butyl n-butyl OH H4-fluorophenyl 1205 n-butyl n-butyl OH H

1206 n-butyl n-butyl OH H

1207 n-butyl n-butyl OH H 3,5-dichlorophenyl 1208 n-butyl n-butyl OH H4-methoxyphenyl 1209 n-butyl n-butyl acetoxy H phenyl 1210 n-butyln-butyl OH H 2-(dimethylamino)phenyl 1211 ethyl n-butyl OH H

1212 n-butyl n-butyl OH H 4-methoxyphenyl 1213 n-butyl ethyl H OH H 1214n-butyl ethyl OH H phenyl 1215 n-butyl n-butyl OH H 4-methoxyphenyl 1216ethyl n-butyl OH H 5-piperonyl 1217 n-butyl n-butyl OH H 4-carboxyphenyl1218 n-butyl n-butyl OH H 4-methoxyphenyl 1219 n-butyl n-butyl OH H

1220 n-butyl n-butyl OH H 3-methoxyphenyl 1221 n-butyl n-butyl OH H

1222 n-butyl n-butyl OH H 3-methoxyphenyl 1223 n-butyl n-butyl OH Hphenyl 1224 n-butyl n-butyl OH H 3-nitrophenyl 1225 n-butyl ethyl OH H3-methylphenyl 1226 ethyl n-butyl OH H 5-piperonyl 1227 n-butyl n-butylOH H 4-fluorophenyl 1228 n-butyl n-butyl OH H 2-pyrrolyl 1229 n-butyln-butyl OH H 3-chloro-4-hydroxyphenyl 1230 n-butyl n-butyl OH H phenyl1231 n-butyl n-butyl OH H

1232 n-butyl n-butyl H OH 3-thiophenyl 1233 n-butyl n-butyl OH H

1234 n-butyl n-butyl OH H

1235 n-butyl n-butyl OH H

1236 n-butyl n-butyl OH H 4-(bromomethyl)phenyl 1237 n-butyl n-butyl OHH

1238 n-butyl n-butyl OH H

1239 n-butyl n-butyl OH H

1240 n-butyl n-butyl OH H 4-methoxy-3-methylphenyl 1241 n-butyl n-butylOH H 3-(dimethylaminomethly)phenyl 1242 n-butyl n-butyl OH H

1243 n-butyl n-butyl OH H

1244 n-butyl n-butyl OH H 3-methoxyphenyl 1245 n-butyl n-butyl OH H

1246 n-butyl n-butyl OH H 3-(bromomethyl)phenyl 1247 n-butyl n-butyl OHH

1248 n-butyl n-butyl OH H

1249 n-butyl n-butyl OH H

1250 n-butyl n-butyl OH H 3-(dimethylamino)phenyl 1251 n-butyl n-butylOH H 1-naphthyl 1252 n-butyl n-butyl OH H

1253 n-butyl n-butyl OH H

1254 n-butyl n-butyl OH H

1255 n-butyl n-butyl OH H

1256 n-butyl n-butyl OH H 3-nitrophenyl 1257 n-butyl n-butyl OH H phenyl1258 n-butyl n-butyl OH H 4-fluorophenyl 1259 ethyl n-butyl H OH H 1260ethyl n-butyl OH H 3-hydroxyphenyl 1261 n-butyl n-butyl OH H

1262 n-butyl n-butyl OH H 2-thiophenyl 1263 n-butyl n-butyl OH H5-piperonyl 1264 n-butyl n-butyl OH H 4-fluorophenyl 1265 n-butyln-butyl OH H 4-fluorophenyl 1266 n-butyl n-butyl OH H

1267 n-butyl ethyl OH H 5-piperonyl 1268 n-butyl n-butyl OH H

1269 n-butyl n-butyl OH H

1270 n-butyl n-butyl OH H

1271 n-butyl n-butyl OH H

1272 n-butyl n-butyl OH H

1273 n-butyl n-butyl OH H

1274 n-butyl n-butyl OH H

1275 n-butyl n-butyl OH H

1276 n-butyl n-butyl OH H

1277 n-butyl n-butyl OH H

1278 n-butyl n-butyl OH H

1279 n-butyl n-butyl OH H

1280 n-butyl n-butyl OH H

1281 n-butyl n-butyl OH H

1282 ethyl n-butyl OH H 3-fluoro-4-methoxyphenyl 1283 n-butyl n-butyl OHH 4-hydroxymethylphenyl 1284 n-butyl n-butyl OH H 4-fluorophenyl 1285n-butyl ethyl OH H phenyl 1286 n-butyl n-butyl OH H

1287 n-butyl ethyl OH H 4-hydroxyphenyl 1288 n-butyl n-butyl OH H

1289 n-butyl n-butyl OH H

1290 n-butyl n-butyl OH H

1291 n-butyl n-butyl OH H

1292 n-butyl n-butyl OH H

1293 n-butyl n-butyl OH H

1294 n-butyl n-butyl OH H

1295 n-butyl n-butyl OH H

1296 n-butyl n-butyl OH H

1297 n-butyl n-butyl OH H

1298 n-butyl n-butyl OH H

1299 n-butyl n-butyl OH H

1300 n-butyl ethyl H OH H 1301 n-butyl n-butyl OH H 3-methoxyphenyl 1302n-butyl n-butyl OH H 3-hydroxyphenyl 1303 n-butyl n-butyl OH H

1304 n-butyl n-butyl OH H 3-methoxyphenyl 1305 n-butyl n-butyl OH H4-fluorophenyl 1306 n-butyl n-butyl OH H

1307 n-butyl n-butyl OH H H 1308 ethyl n-butyl OH H

1309 n-butyl n-butyl OH H 4-methoxyphenyl 1310 ethyl n-butyl OH H phenyl1311 n-butyl ethyl OH H phenyl 1312 n-butyl ethyl OH H phenyl 1313n-butyl ethyl OH H phenyl 1314 ethyl n-butyl OH H phenyl 1315 ethyln-butyl OH H phenyl 1316 n-butyl ethyl OH H phenyl 1317 n-butyl ethyl OHH phenyl 1318 ethyl n-butyl OH H phenyl 1319 ethyl n-butyl OH H3-methoxyphenyl 1320 ethyl n-butyl OH H phenyl 1321 n-butyl ethyl OH Hphenyl 1322 n-butyl n-butyl OH H

1323 n-butyl n-butyl OH H

1324 n-butyl n-butyl OH H

1325 n-butyl n-butyl OH H 4-((diethylamino)methyl)phenyl 1326 n-butyln-butyl OH H

1327 n-butyl n-butyl OH H 3-fluoro-4-hydroxy-5-iodophenyl 1328 n-butyln-butyl OH H

1329 n-butyl n-butyl OH H

1330 n-butyl n-butyl OH H

1331 n-butyl n-butyl OH H

1332 n-butyl n-butyl OH H

1333 n-butyl n-butyl OH H

1334 n-butyl n-butyl OH H

1335 n-butyl n-butyl OH H

1336 n-butyl n-butyl OH H

1337 n-butyl n-butyl OH H

1338 n-butyl n-butyl OH H 4-methoxyphenyl 1339 n-butyl n-butyl OH H

1340 n-butyl ethyl OH H 5-piperonyl 1341 n-butyl n-butyl acetoxy H3-methoxyphenyl 1342 n-butyl n-butyl OH H 5-piperonyl 1343 ethyl n-butylOH H phenyl 1344 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl 1345ethyl n-butyl OH H phenyl 1346 ethyl n-butyl OH H phenyl 1347 n-butyln-butyl OH H 3-fluoro-4-methoxyphenyl 1348 isobutyl isobutyl OH H phenyl1349 ethyl n-butyl OH H phenyl 1350 n-butyl n-butyl OH H3-fluoro-4-methoxyphenyl 1351 n-butyl n-butyl OH H

1352 n-butyl n-butyl OH H

1353 n-butyl n-butyl OH H

1354 n-butyl n-butyl OH H

1355 n-butyl n-butyl OH H

1356 n-butyl n-butyl OH H

1357 n-butyl n-butyl OH H

1358 n-butyl n-butyl OH H

1359 n-butyl n-butyl OH H

1360 n-butyl n-butyl OH H

1361 n-butyl n-butyl OH H

1362 n-butyl n-butyl OH H

1363 n-butyl n-butyl OH H

1364 n-butyl n-butyl OH H

1365 n-butyl n-butyl OH H

1366 n-butyl n-butyl OH H

1367 n-butyl n-butyl OH H

1368 n-butyl n-butyl OH H

1369 n-butyl n-butyl OH H

1370 n-butyl n-butyl OH H

1371 n-butyl n-butyl OH H

1372 n-butyl n-butyl OH H

1373 n-butyl n-butyl OH H

1374 n-butyl n-butyl OH H

1375 n-butyl n-butyl OH H

1376 n-butyl n-butyl OH H

1377 n-butyl n-butyl OH H

1378 n-butyl n-butyl OH H

1379 n-butyl n-butyl OH H

1380 n-butyl n-butyl OH H

1381 n-butyl n-butyl OH H

1382 n-butyl n-butyl OH H

1383 n-butyl n-butyl OH H

1384 n-butyl n-butyl OH H

1385 n-butyl n-butyl OH H

1386 n-butyl n-butyl OH H

1387 n-butyl n-butyl OH H

1388 n-butyl n-butyl OH H

1389 n-butyl n-butyl OH H

1390 n-butyl n-butyl OH H

1391 n-butyl n-butyl OH H

1392 n-butyl n-butyl OH H

1393 n-butyl n-butyl OH H

1394 n-butyl n-butyl OH H

1395 n-butyl n-butyl OH H

1396 n-butyl n-butyl OH H

1397 n-butyl n-butyl OH H

1398 n-butyl n-butyl OH H

1399 n-butyl n-butyl OH H

1400 n-butyl n-butyl OH H

1401 n-butyl n-butyl OH H

1402 n-butyl n-butyl OH H

1403 n-butyl n-butyl OH H

1404 n-butyl n-butyl OH H

1405 n-butyl n-butyl OH H

1406 n-butyl n-butyl OH H

1407 n-butyl n-butyl OH H

1408 n-butyl n-butyl OH H

1409 n-butyl n-butyl OH H

1410 n-butyl n-butyl OH H

1411 n-butyl n-butyl OH H

1412 n-butyl n-butyl OH H

1413 n-butyl n-butyl OH H

1414 n-butyl n-butyl OH H

1415 n-butyl n-butyl OH H

1416 n-butyl n-butyl OH H

1417 n-butyl n-butyl OH H

1418 n-butyl n-butyl OH H

1419 n-butyl n-butyl OH H

1420 n-butyl n-butyl OH H

1421 n-butyl n-butyl OH H

1422 n-butyl n-butyl OH H

1423 n-butyl n-butyl OH H

1424 n-butyl n-butyl OH H

1425 n-butyl n-butyl OH H

1426 n-butyl n-butyl OH H

1427 n-butyl n-butyl OH H

1428 n-butyl n-butyl OH H

1429 n-butyl n-butyl OH H

1430 n-butyl n-butyl OH H

1431 n-butyl n-butyl OH H

1432 n-butyl n-butyl OH H

1433 n-butyl n-butyl OH H

1434 n-butyl n-butyl OH H

1435 n-butyl n-butyl OH H

1436 n-butyl n-butyl OH H

1437 n-butyl n-butyl OH H

1438 n-butyl n-butyl OH H

1439 n-butyl n-butyl OH H

1440 n-butyl n-butyl OH H

1441 n-butyl n-butyl OH H

1442 n-butyl n-butyl OH H

1443 n-butyl n-butyl OH H

1444 n-butyl n-butyl OH H

1445 n-butyl n-butyl OH H

1446 n-butyl n-butyl OH H

1447 n-butyl n-butyl OH H

1448 n-butyl n-butyl OH H

1449 n-butyl n-butyl OH H

1450 n-butyl n-butyl OH H phenyl 1451 n-butyl n-butyl OH H

[0227] Compound Number R⁶ (R^(x))q 101 H

at the 7-position 102 H 7-trimethylammonium iodide 103 H7-trimethylammonium iodide 104 H 7-dimethylamino 105 H7-methanesulfonamido 106 H 7-(2′-bromoacetamido) 107 H 7-amino 108 H7-(hexylamido) 109 H 7-amino 110 H 7-acetamido 111 H 7-amino 112 H7-amino 113 H 7-amino 114 H 7-amino 115 H 7-(O-benzylcarbamato) 116 H7-(O-benzylcarbamato) 117 H 7-(O-benzylcarbamato) 118 H7-(O-benzylcarbamato) 119 H 7-(O-tert-butylcarbamato) 120 H7-(O-benzylcarbamato) 121 H 7-amino 122 H 7-amino 123 H 7-hexylamino 124H 7-(hexylamino) 125 H

at the 8-position 126 H 7-(O-benzylcarbamato) 127 H 7-amino 128 H7-(O-benzylcarbamato) 129 H 7-amino 131 H

at the 7-position 132 H

at the 8-position 133 H 8-(hexyloxy) 134 H

at the 8-position 135 H

at the 8-position 136 H 8-hydroxy 137 H

at the 7-position 138 H 8-acetoxy 139 H

at the 7-position 140 141 142 3-methoxy- 7-methylmercapto phenyl 143 H7-methylmercapto 144 H 7-(N-azetidinyl) 262 H 7-methoxy 263 3-methoxy-7-methoxy phenyl 264 H 7-methoxy 265 3- 7-methoxy trifluoro- methyl-phenyl 266 H 7-hydroxy 267 H 7-methoxy 268 H 7-methoxy 269 4-fluoro-7-methoxy phenyl 270 H 7-hydroxy 271 H 7 -bromo 272 3-methoxy- 7-bromophenyl 273 4-fluoro- 7-fluoro phenyl 274 H 7-fluoro 275 3-methoxy-7-fluoro phenyl 276 H 7-fluoro 277 H 7-methoxy 278 H 7-methoxy 279 H7-methoxy 280 H 7-methoxy 281 H 7-methylmercapto 282 H 7-methyl 2834-fluoro- 7-methyl phenyl 284 H 7-(4′-morpholino) 286 H7-(O-benzylcarbamato) 287 H 7-amino 288 H 7-amino 289 H 7-amino 290 H7-amino 291 H 7-(O-benzylcarbamato) 292 H 7-amino 293 H 7-benzylamino294 H 7-dimethylamino 295 H 7-amino 296 H 7-amino 1000 H 7-dimethylamino1001 H 7-dimethylamino 1002 H 7-dimethylamino 1003 H 7-dimethylamino1004 H 7-dimethylamino 1005 H 7-dimethylamino 1006 H 7-dimethylamino1007 H 7-dimethylamino 1008 H 7-dimethylamino 1009 H 7-dimethylamino1010 H 7-dimethylamino 1011 H 7-dimethylamino 1012 H 7-dimethylamino;9-methoxy 1013 H 7-dimethylamino 1014 H 7-dimethylamino; 9-methoxy 1015H 7-dimethylamino 1016 H 7-dimethylamino 1017 H 7-dimethylamino 1018 H7-dimethylamino 1019 H 7-dimethylamino 1020 H 7-dimethylamino 1021 H7-dimethylamino 1022 H 7-dimethylamino 1023 H 7-dimethylamino 1024 H7-dimethylamino 1025 H 7-dimethylamino 1026 H 7-dimethylamino 1027 H7-dimethylamino 1028 H 7-dimethylamino 1029 H 7-dimethylamino 1030 H7-dimethylamino 1031 H 7-dimethylamino 1032 H 7-dimethylamino 1033 H7-dimethylamino 1034 H 7-dimethylamino 1035 H 7-dimethylamino 1036 H7-dimethylamino 1037 H 7-dimethylamino 1038 H 7-dimethylamino 1039 H7-dimethylamino 1040 H 7-dimethylamino 1041 H 7-dimethylamino 1042 H7-dimethylamino 1043 H 7-dimethylamino 1044 H 7-dimethylamino 1045 H7-dimethylamino 1046 H 7-dimethylamino 1047 H 7-dimethylamino 1048 H7-dimethylamino 1049 H 7-dimethylamino 1050 H 7-dimethylamino 1051 H7-dimethylamino 1052 H 7-dimethylamino 1053 H 7-dimethylamino 1054 H7-dimethylamino 1055 H 7-dimethylamino 1056 H 7-dimethylamino 1057 H7-dimethylamino 1058 H 7-dimethylamino 1059 H 7-dimethylamino 1060 H7-methylamino 1061 H 7-methylamino 1062 H 7-methylamino 1063 H7-methylamino 1064 H 7-methylamino 1065 H 7-dimethylamino 1066 H9-dimethylamino 1067 H 7-dimethylamino 1068 H 7-dimethylamino 1069 H7-dimethylamino; 9-dimethylamino 1070 H 7-dimethylamino 1071 H7-dimethylamino 1072 H 7-dimethylamino 1073 H 7-dimethylamino 1074 H7-dimethylamino 1075 H 7-dimethylamino; 9-dimethylamino 1076 H7-dimethylamino 1077 H 7-dimethylamino 1078 H 7-dimethylamino 1079 H7-dimethylamino 1080 H 7-dimethylamino 1081 H 7-dimethylamino 1082 H7-dimethylamino 1083 H 7-dimethylamino 1084 H 7-dimethylamino 1085 H7-dimethylamino 1086 H 7-dimethylamino 1087 H 7-dimethylamino 1088 H7-dimethylamino 1089 H 7-dimethylamino 1090 H 7-dimethylamino 1091 H7-dimethylamino 1092 H 7-dimethylamino 1093 H 7-dimethylamino 1094 H7-dimethylamino 1095 H 7-dimethylamino 1096 H 7-dimethylamino 1097 H7-dimethylamino 1098 H 7-dimethylamino 1099 H 7-dimethylamino 1100 H7-dimethylamino 1101 H 7-dimethylamino 1102 H 7-dimethylamino 1103 H7-dimethylamino 1104 H 7-dimethylamino 1105 H 7-dimethylamino 1106 H7-dimethylamino 1107 H 7-dimethylamino 1108 H 7-dimethylamino 1109 H7-dimethylamino 1110 H 7-dimethylamino 1111 H 7-dimethylamino 1112 H7-dimethylamino 1113 H 7-dimethylamino 1114 H 7-methylamino 1115 H7-dimethylamino 1116 H 7-dimethylamino 1117 H 7-dimethylamino 1118 H7-dimethylamino 1119 H 7-dimethylamino 1120 H 7-dimethylamino 1121 H7-dimethylamino 1122 H 7-dimethylamino 1123 H 7-dimethylamino 1124 H7-dimethylamino 1125 H 7-dimethylamino 1126 H 7-dimethylamino 1127 H7-dimethylamino 1128 H 7-dimethylamino 1129 H 9-dimethylamino 1130 H7-dimethylamino 1131 H 7-dimethylamino 1132 H 7-dimethylamino 1133 H7-dimethylamino 1134 H 7-dimethylamino 1135 H 7-dimethylamino 1136 H7-dimethylamino 1137 H 9-(2′,2′-dimethylhydrazino) 1138 H7-dimethylamino 1139 H 7-dimethylamino 1140 H7-(2′,2′-dimethylhydrazino) 1141 H 7-ethylmethylamino 1142 H7-dimethylamino 1143 3-fluoro- 7-dimethylamino 4-methoxy- phenyl 1144 H7-dimethylamino 1145 H 9-dimethylamino 1146 H 7-dimethylamino 1147 H7-diethylamino 1148 H 7-dimethylsulfonium, fluoride salt 1149 H7-ethylamino 1150 H 7-ethylmethylamino 1151 H 7-dimethylamino 1152 H7-(ethoxymethyl) methylamino 1153 H 7-methylamino 1154 H 9-methoxy 1155H 7-methyl 1156 H 7-methylmercapto 1157 H 7-fluoro; 9-dimethylamino 1158H 7-methoxy 1159 H 7-dimethylamino 1160 H 7-diethylamino 1161 H7-dimethylamino 1162 H 7-dimethylamino 1163 H 7-methoxy 1164 H 7-methoxy1165 H 7-trimethylammonium iodide 1166 H 7-trimethylammonium iodide 1167H 7-dimethylamino 1168 H 7-trimethylammonium iodide 1169 H8-dimethylamino 1170 H 7-ethylpropylamino 1171 H 7-dimethylamino 1172 H7-methoxy 1173 H 7-ethylpropylamino 1174 H 7-phenyl 1175 H7-methylsulfonyl 1176 H 9-fluoro 1177 H 7-butylmethylamino 1178 H7-dimethylamino 1179 H 8-methoxy 1180 H 7-trimethylammonium iodide 1181H 7-butylmethylamino 1182 H 7-methoxy 1183 H 7-fluoro 1184 H 7-fluoro;9-fluoro 1185 H 7-fluoro 1186 H 7-fluoro; 9-fluoro 1187 H 7-methyl 1188H 7-trimethylammonium iodide 1189 H 7-trimethylammonium iodide 1190 H7-bromo 1191 H 7-hydroxy 1192 H 7-hydroxy 1193 H 7-dimethylamino 1194 H7-dimethylamino 1195 H 7-(4′-methylpiperazin-1-yl) 1196 H 7-methoxy 1197H 7-(N-methylformamido) 1198 H 7-methoxy 1199 H 7-dimethylamino 1200phenyl 7-dimethylamino 1201 H 7-methyl 1202 H 7-methoxy 1203 H7-(4′-tert-butylphenyl) 1204 H 7-methoxy 1205 H 7-dimethylamino 1206 H7-dimethylamino 1207 H 7-dimethylamino 1208 H 7-dimethylamino 1209 H7-dimethylphenyl 1210 H 7-dimethylamino 1211 H 7-dimethylamino 1212 H9-(4′-morpholino) 1213 3-fluoro- 7-dimethylamino 4-methoxy- phenyl 1214H 7-(N-methylformamido) 1215 H 9-methylmercapto 1216 H 7-bromo 1217 H7-dimethylamino 1218 H 9-methylsulfonyl 1219 H 7-dimethylamino 1220 H7-isopropylamino 1221 H 7-dimethylamino 1222 H 7-ethylamino 1223 H8-bromo; 7-methylamino 1224 H 7-fluoro 1225 H 7-dimethylamino 1226 H7-bromo 1227 H 7-(tert-butylamino 1228 H 8-bromo; 7-dimethylamino 1229 H7-dimethylamino 1230 H 9-dimethylamino; 7-fluoro 1231 H 7-dimethylamino1232 H 9-dimethylamino 1233 H 7-dimethylamino 1234 H 7-dimethylamino1235 H 7-dimethylamino 1236 H 7-dimethylamino 1237 H 7-dimethylamino1238 H 7-dimethylamino 1239 H 7-dimethylamino 1240 H 7-dimethylamino1241 H 7-dimethylamino 1242 H 7-dimethylamino 1243 H 7-dimethylamino1244 H 7-(1′-methylhydrazido) 1245 H 7-dimethylamino 1246 H7-dimethylamino 1247 H 7-dimethylamino 1248 H 7-dimethylamino 1249 H7-dimethylamino 1250 H 7-dimethylamino 1251 H 7-dimethylamino 1252 H7-dimethylamino 1253 H 7-dimethylamino 1254 H 7-dimethylamino 1255 H7-dimethylamino 1256 H 7-dimethylamino 1257 H 8-bromo; 7-dimethylamino1258 H 9-(tert-butylamino) 1259 phenyl 7-dimethylamino 1260 H7-dimethylamino 1261 H 7-dimethylamino 1262 H 7-dimethylamino 1263 H7-bromo 1264 H 7-isopropylamino 1265 H 9-isopropylamino 1266 H7-dimethylamino 1267 H 7-carboxy, methyl ester 1268 H 7-dimethylamino1269 H 7-dimethylamino 1270 H 7-dimethylamino 1271 H 7-dimethylamino1272 H 7-dimethylamino 1273 H 7-dimethylamino 1274 H 7-dimethylamino1275 H 7-dimethylamino 1276 H 7-dimethylamino 1277 H 7-dimethylamino1278 H 7-dimethylamino 1279 H 7-dimethylamino 1280 H 7-dimethylamino1281 H 7-dimethylamino 1282 H 7-trimethylammonium iodide 1283 H7-dimethylamino 1284 H 9-ethylamino 1285 H 7-dimethylamino 1286 H7-dimethylamino 1287 H 7-dimethylamino 1288 H 7-dimethylamino 1289 H7-dimethylamino 1290 H 7-dimethylamino 1291 H 7-dimethylamino 1292 H7-dimethylamino 1293 H 7-dimethylamino 1294 H 7-dimethylamino 1295 H7-dimethylamino 1296 H 7-dimethylamino 1297 H 7-dimethylamino 1298 H7-dimethylamino 1299 H 7-dimethylamino 1300 phenyl 7-dimethylamino 1301H 7-trimethylammonium iodide 1302 H 9-hydroxy 1303 H 7-dimethylamino1304 H 7-tert-butylamino 1305 H 9-methylamino 1306 H 7-dimethylamino1307 4-methoxy- 9-(4′-morpholino) phenyl 1308 H 7-dimethylamino 1309 H9-fluoro 1310 H 7-amino 1311 H 7-(hydroxylamino) 1312 H 8-hexyloxy 1313H 8-ethoxy 1314 H 7-(hydroxylamino) 1315 H 7-(hexyloxy) 1316 H 8-hydroxy1317 H

at the 8-position 1318 H 7-dimethylamino 1319 H 7-fluoro 1320 H 7-amino1321 H

at the 8-position 1322 H 7-dimethylamino 1323 H 7-dimethylamino 1324 H7-dimethylamino 1325 H 7-dimethylamino 1326 H 7-dimethylamino 1327 H7-dimethylamino 1328 H 7-dimethylamino 1329 H 7-dimethylamino 1330 H7-dimethylamino 1331 H 7-dimethylamino 1332 H 7-dimethylamino 1333 H7-dimethylamino 1334 H 7-dimethylamino 1335 H 7-dimethylamino 1336 H7-dimethylamino 1337 H 7-dimethylamino 1338 H 7-(4′-methylpiperazinyl)1339 H 7-dimethylamino 1340 H 7-methyl 1341 H 7-dimethylamino 1342 H7-(4′-fluorophenyl) 1343 H 7-amino 1344 H 7-dimethylamino 1345 H7-trimethylammonium iodide 1346 H

at the 8-position 1347 H 7-dimethylamino 1348 H 7-dimethylamino 1349 H7-dimethylamino 1350 H 7-trimethylammonium iodide 1351 H 7-dimethylamino1352 H 7-dimethylamino 1353 H 7-dimethylamino 1354 H 7-dimethylamino1355 H 7-dimethylamino 1356 H 7-dimethylamino 1357 H 7-dimethylamino1358 H 7-dimethylamino 1359 H 7-dimethylamino 1360 H 7-dimethylamino1361 H 7-dimethylamino 1362 H 7-dimethylamino 1363 H 7-dimethylamino1364 H 7-dimethylamino 1365 H 7-dimethylamino 1366 H 7-dimethylamino1367 H 7-dimethylamino 1368 H 7-dimethylamino 1369 H 7-dimethylamino1370 H 7-dimethylamino 1371 H 7-dimethylamino 1372 H 7-dimethylamino1373 H 7-dimethylamino 1374 H 7-dimethylamino 1375 H 7-dimethylamino1376 H 7-dimethylamino 1377 H 7-dimethylamino 1378 H 7-dimethylamino1379 H 7-dimethylamino 1380 H 7-dimethylamino 1381 H 7-dimethylamino1382 H 7-dimethylamino 1383 H 7-dimethylamino 1384 H 7-dimethylamino1385 H 7-dimethylamino 1386 H 7-dimethylamino 1387 H 7-dimethylamino1388 H 7-dimethylamino 1389 H 7-dimethylamino 1390 H 7-dimethylamino1391 H 7-dimethylamino 1392 H 7-dimethylamino 1393 H 7-dimethylamino1394 H 7-dimethylamino 1395 H 7-dimethylamino 1396 H 7-dimethylamino1397 H 7-dimethylamino 1398 H 7-dimethylamino 1399 H 7-dimethylamino1400 H 7-dimethylamino 1401 H 7-dimethylamino 1402 H 7-dimethylamino1403 H 7-dimethylamino 1404 H 7-dimethylamino 1405 H 7-dimethylamino1406 H 7-dimethylamino 1407 H 7-dimethylamino 1408 H 7-dimethylamino1409 H 7-dimethylamino 1410 H 7-dimethylamino 1411 H 7-dimethylamino1412 H 7-dimethylamino 1413 H 7-dimethylamino 1414 H 7-dimethylamino1415 H 7-dimethylamino 1416 H 7-dimethylamino 1417 H 7-dimethylamino1418 H 7-dimethylamino 1419 H 7-dimethylamino 1420 H 7-dimethylamino1421 H 7-dimethylamino 1422 H 7-dimethylamino 1423 H 7-dimethylamino1424 H 7-dimethylamino 1425 H 7-dimethylamino 1426 H 7-dimethylamino1427 H 7-dimethylamino 1428 H 7-dimethylamino 1429 H 7-dimethylamino1430 H 7-dimethylamino 1431 H 7-dimethylamino 1432 H 7-dimethylamino1433 H 7-dimethylamino 1434 H 7-dimethylamino 1435 H 7-dimethylamino1436 H 7-dimethylamino 1437 H 7-dimethylamino 1438 H 7-dimethylamino1439 H 7-dimethylamino 1440 H 7-dimethylamino 1441 H 7-dimethylamino1442 H 7-dimethylamino 1443 H 7-dimethylamino 1444 H 7-dimethylamino1445 H 7-dimethylamino 1446 H 7-methoxy; 8-methoxy 1447 H7-dimethylamino 1448 H 7-dimethylamino 1449 H 7-dimethylamino 1450 H7-dimethylamino 1451 H 7-dimethylamino

[0228]

[0229] In further compounds of the present invention, R⁵ and R⁶ areindependently selected from among hydrogen and ring-carbon substitutedor unsubstituted aryl, thiophene, pyridine, pyrrole, thiazole,imidazole, pyrazole, pyrimidine, morpholine, N-alkylpyridinium,N-alkylpiperazinium, N-alkylmorpholinium, or furan in which thesubstituent(s) are selected from among halo, hydroxyl, trihaloalkyl,alkoxy, amino, N-alkylamino, N,N-dialkylamino, quaternary ammoniumsalts, a C₁ to C₄ alkylene bridge having a quaternary ammonium saltsubstituted thereon, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyloxyand arylcarbonyloxy, (O,O)-dioxyalkylene,

[0230] —[O(CH₂)_(w)]_(x)X where x is 2 to 12, w is 2 or 3 and Xcomprises halo or a quaternary ammonium salt, thiophene, pyridine,pyrrole, thiazole, imidazole, pyrazole, or furan. The aryl group of R⁵or R⁶ is preferably phenyl, phenylene, or benzene triyl, i.e., may beunsubstituted, mono-substituted, or di-substituted. Among the specieswhich may constitute the substituents on the aryl ring of R⁵ or R⁶ arefluoro, chloro, bromo, methoxy, ethoxy, isopropoxy, trimethylammonium(preferably with an iodide or chloride counterion), methoxycarbonyl,ethoxycarbonyl, formyl, acetyl, propanoyl, (N)-hexyldimethylammonium,hexylenetrimethylammonium, tri(oxyethylene)iodide, andtetra(oxyethylene)trimethyl-ammonium iodide, each substituted at thep-position, the m-position, or both of the aryl ring. Other substituentsthat can be present on a phenylene, benzene triyl or other aromatic ringinclude 3,4-dioxymethylene (5-membered ring) and 3,4-dioxyethylene(6-membered ring). Among compounds which have been or can bedemonstrated to have desirable ileal bile acid transport inhibitingproperties are those in which R⁵ or R⁶ is selected from phenyl,p-fluorophenyl, m-fluorophenyl, p-hydroxyphenyl, m-hydroxyphenyl,p-methoxyphenyl, m-methoxyphenyl, p-N,N-dimethylaminophenyl,m-N,N-dimethylaminophenyl, I⁻ p-(CH₃)₃-N⁺-phenyl, I⁻ m-(CH₃)₃-N⁺-phenyl, I⁻ m-(CH₃)₃-N⁺—CH₂CH₂—(OCH₂CH₂)₂-O-phenyl, I⁻ p-(CH₃)₃-N^(+—CH) ₂CH₂—(OCH₂CH₂)₂-O-phenyl, I⁻ m-(N,N-dimethylpiperazinium)-(N′)—CH₂—(OCH₂CH₂)₂-O-phenyl,3-methoxy-4-fluorophenyl, thienyl-2-yl, 5-cholorothienyl-2-yl,3,4-difluorophenyl, I⁻p-(N,N-dimethylpiperazinium)-(N′)—CH₂—(OCH₂CH₂)₂-O-phenyl,3-fluoro-4-methoxyphenyl, -4-pyridinyl, 2-pyridinyl, 3-pyridinyl,N-methyl-4-pyridinium, I⁻ N-methyl-3-pyridinium,3,4-dioxymethylenephenyl, 3,4-dioxyethylenephenyl, andp-methoxycarbonylphenyl. Preferred compounds include 3-ethyl-3-butyl and3-butyl-3-butyl compounds having each of the above preferred R⁵substituents in combination with the R_(x) substituents shown inTable 1. It is particularly preferred that one but not both of R⁵ and R⁶is hydrogen.

[0231] It is especially preferred that R⁴ and R⁶ be hydrogen, that R³and R⁵ not be hydrogen, and that R³ and R⁵ be oriented in the samedirection relative to the plane of the molecule, i.e., both in α- orboth in β-configuration. It is further preferred that, where R² is butyland R¹ is ethyl, then R¹ has the same orientation relative to the planeof the molecule as R³ and R⁵.

[0232] Set forth in Table 1A are lists of species of R¹/R², R⁵/R⁶ andR^(x). TABLE 1A Alternative R Groups

R¹, R² R³, R⁴ R⁵ (R^(x))q ethyl HO— Ph— 7-methyl n-propyl H— p-F—Ph—7-ethyl n-butyl m-F—Ph— 7-iso-propyl n-pentyl p-CH₃O—Ph— 7-tert-butyln-hexyl p-CH₃O—Ph— 7-OH iso-propyl m-CH₃O—Ph— 7-OCH₃ iso-butylp-(CH₃)₂N—Ph— 7-O(iso-propyl) iso-pentyl m-(CH₃)₂N—Ph— 7-SCH₃CH₂C(═O)C₂H₅ I⁻, p-(CH₃)₃—N⁺—Ph— 7-SOCH₃ CH₂OC₂H₅ I⁻, m-(CH₃)₃—N⁺—Ph—7-SO₂CH₃ CH₂CH(OH)C₂H₅ I⁻, p-(CH₃)₃—N⁺—CH₂CH₂— 7-SCH₂CH₃CH₂O-(4-picoline) (OCH₂CH₂)₂—O—Ph— 7-NH₂ I⁻, m-(CH₃)₃—N⁺—CH₂CH₂— 7-NHOH(OCH₂CH₂)₂—O—Ph— 7-NHCH₃ I⁻, p-(N,N- 7-N(CH₃)₂ dimethylpiperazine)-7-N⁺(CH₃)₃, I⁻ (N′)—CH₂—(OCH₂CH₂)₂—O— 7-NHC(═O)CH₃ Ph— 7-N(CH₂CH₃)₂ I⁻,m-(N,N- 7-NMeCH₂CO₂H dimethylpiperazine)- 7-N⁺(Me)₂CH₂CO₂H, I⁻(N′)—CH₂—(OCH₂CH₂)₂—O— 7-(N)-morpholine Ph— 7-(N)-azetidine m-F,p-CH₃O—Ph— 7-(N)—N-methylazetidinium, 3,4, dioxymethylene-Ph I⁻ m-CH₃O—,p-F—Ph— 7-(N)-pyrrolidine 4-pyridine 7-(N)—N-methyl-N-methyl-4-pyridinium, I⁻ pyrrolidinium, I⁻ 3-pyridine 7-(N)—N-methyl-N-methyl-3-pyridinium, I⁻ morpholinium, I⁻ 2-pyridine7-(N)—N′-methylpiperazine p-CH₃O₂C—Ph— 7-(N)—N′- thienyl-2-yldimethylpiperazinium, 5-Cl-thienyl-2-yl I⁻ 7-NH—CBZ 7-NHC(O)C₅H₁₁7-NNO(O)CH₂Br 7-NH—C(NH)NH₂ 7-(2)-thiophene 8-methyl 8-ethyl8-iso-propyl 8-tert-butyl 8-OH 8-OCH₃ 8-O(iso-propyl) 8-SCH₃ 8-SOCH₃8-SO₂CH₃ 8-SCH₂CH₃ 8-NH₂ 8-NHOH 8-NHCH₃ 8-N(CH₃)₂ 8-N⁺(CH₃)₃, I⁻8-NHC(═O)CH₃ 8-N(CH₂CH₃)₂ 8-NMeCH₂CO₂H 8-N⁺(Me)₂CH₂CO₂H, I⁻8-(N)-morpholine 8-(N)-azetidine 8-(N)—N-methylazetidinium, I⁻8-(N)-pyrrolidine 8-(N)—N-methyl- pyrrolidinium, I⁻ 8-(N)—N-methyl-morpholinium, I⁻ 8-(N)—N′-methylpiperazine 8-(N)—N′-dimethylpiperazinium, I⁻ 8-NH—CBZ 8-NHC(O)C₅H₁₁ 8-NHC(O)CH₂Br8-NH—C(NH)NH₂ 8-(2)-thiophene 9-methyl 9-ethyl 9-iso-propyl 9-tert-butyl9-OH 9-OCH₃ 9-O(iso-propyl) 9-SCH₃ 9-SOCH₂ 9-SO₂CH₃ 9-SCH₂CH₃ 9-NH₂9-NHOH 9-NHCH₃ 9-N(CH₃)₂ 9-N⁺(CH₃)₃, I⁻ 9-NHC(═O)CH₃ 9-N(CH₂CH₃)₂9-NMeCH₂CO₂H 9-N⁺(Me)₂CH₂CO₂H, I⁻ 9-(N)-morpholine 9-(N)-azetidine9-(N)—N-methylazetidinium, I⁻ 9-(N)-pyrrolidine 9-(N)—N-methyl-pyrrolidinium, I⁻ 9-(N)—N-methyl- morpholinium, I⁻9-(N)—N′-methylpiperazine 9-(N)—N′- dimethylpiperaziniuim, I⁻ 9-NH—CBZ9-NHC(O)C₅H₁₁ 9-NHC(O)CH₂Br 9-NH—C(NH)NH₂ 9-(2)-thiophene 7-OCH₃, 8-OCH₃7-SCH₃, 8-OCH₃ 7-SCH₃, 8-SCH₃ 6-OCH₃, 7-OCH₃, 8-OCH₃

[0233] Further preferred compounds of the present invention comprise acore structure having two or more pharmaceutically active benzothiepinestructures as described above, covalently bonded to the core moiety viafunctional linkages. Such active benzothiepine structures preferablycomprise:

[0234] where R¹, R², R³, R⁴, R⁵R⁶, R⁷, R⁸, X, q and n are as definedabove, and R55 is either a covalent bond or arylene.

[0235] The core moiety can comprise alkane diyl, alkene diyl, alkynediyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl,carbohydrate, amino acid, and peptide, polypeptide, wherein alkane diyl,alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl,polyalkoxy diyl, carbohydrate, amino acid, and peptide polypeptide, canoptionally have one or more carbon replaced by O, NR⁷, N⁺R⁷R⁸, S, SO,SO2, S⁺R⁷R⁸, PR7, P+R7R8, phenylene, heterocycle, quatarnaryheterocycle, quaternary heteroaryl, or aryl,

[0236] wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl,alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid,peptide, and polypeptide can be substituted with one or more substituentgroups independently selected from the group consisting of alkyl,alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl,heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³,SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM,SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R15A-,P(OR¹³) OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻;

[0237] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, and heterocycle can be further substituted withone or more substituent groups selected from the group consisting ofOR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸,N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷R⁸,P⁺R⁷R⁸A⁻, and P(O) (OR⁷)OR⁸, and

[0238] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, and heterocycle can optionally have one or morecarbons replaced by O, NR⁷, N⁺R⁷R⁸A-, S, SO, SO₂, S⁺R⁷A-, PR⁷, P(O)R⁷,P⁺R⁷R⁸A-, or phenylene.

[0239] Exemplary core moieties include:

[0240] wherein:

[0241] R²⁵ is selected from the group consisting of C and N, and

[0242] R²⁶ and R²⁷ are independently selected from the group consistingof:

[0243] wherein R²⁶, R²⁷, R³⁰ and R³¹ are independently selected fromalkyl, alkenyl, alkylaryl, aryl, arylalkyl, cycloalkyl, heterocycle, andheterocycloalkyl,

[0244] A⁻ is a pharmaceutically acceptable anion, and k=1 to 10.

[0245] In compounds of Formula DIV, R²⁰ , R²¹ , R²² in Formulae DII andDIII, and R²³ in Formula DIII can be bonded at any of their 6-, 7-, 8-,or 9- positions to R¹⁹. In compounds of Formula DIVA, it is preferredthat R⁵⁵ comprises a phenylene moiety bonded at a m- or p-positionthereof to R¹⁹.

[0246] In another embodiment, a core moiety backbone, R¹⁹, as discussedherein in Formulas DII and DIII can be multiply substituted with morethan four pendant active benzothiepine units, i.e., R²⁰, R²¹, R²², andR²³ as discussed above, through multiple functional groups within thecore moiety backbone. The core moiety backbone unit, R¹⁹, can comprise asingle core moiety unit, multimers thereof, and multimeric mixtures ofthe different core moiety units discussed herein, i.e., alone or incombination. The number of individual core moiety backbone units canrange from about one to about 100, preferably about one to about 80,more preferably about one to about 50, and even more preferably aboutone to about 25. The number of points of attachment of similar ordifferent pendant active benzothiepine units within a single core moietybackbone unit can be in the range from about one to about 100,preferably about one to about 80, more preferably about one to about 50,and even more preferably about one to about 25. Such points ofattachment can include bonds to C, S, O, N, or P within any of thegroups encompassed by the definition of R¹⁹.

[0247] The more preferred benzothiepine moieties comprising R²⁰, R²¹,R²² and/or R²³ conform to the preferred structures as outlined above forFormula I. The 3-carbon on each benzothiepine moiety can be achiral, andthe substituents R¹, R², R³, R⁴, R⁵ and R^(x) can be selected from thepreferred groups and combinations of substituents as discussed above.The core structures can comprise, for example, poly(exyalkylene) oroligo(oxyalkylene), especially poly- or oligo(exyethylene) or poly- oroligo(oxypropylene).

[0248] Dosages, Formulations, and Routes of Administration

[0249] The iheal bile acid transport inhibitor compounds of the presentinvention can be administered for the prophylaxis and treatment ofhyperlipidemic diseases or conditions by any means, preferably oral,that produce contact of these compounds with their site of action in thebody, for example in the ileum of a mammal, e.g., a human.

[0250] For the prophylaxis or treatment of the conditions referred toabove, the compounds of the present invention can be used as thecompound per se.

[0251] Pharmaceutically acceptable salts are particularly suitable formedical applications because of their greater aqueous solubilityrelative to the parent compound. Such salts must clearly have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the present inventionwhen possible include those derived from inorganic acids, such ashydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic,and sulfuric acids, and organic acids such as acetic, benzenesulfonic,benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic,isothionic, lactic, lactobionic, maleic, malic, methanesulfonic,succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. Thechloride salt is particularly preferred for medical purposes. Suitablepharmaceutically acceptable base salts include ammonium salts, alkalimetal salts such as sodium and potassium salts, and alkaline earth saltssuch as magnesium and calcium salts.

[0252] The anions of the definition of A⁻ in the present invention are,of course, also required to be pharmaceutically acceptable and are alsoselected from the above list.

[0253] The compounds of the present invention can be presented with anacceptable carrier in the form of a pharmaceutical composition. Thecarrier must, of course, be acceptable in the sense of being compatiblewith the other ingredients of the composition and must not bedeleterious to the recipient. The carrier can be a solid or a liquid, orboth, and is preferably formulated with the compound as a unit-dosecomposition, for example, a tablet, which can contain from 0.05% to 95%by weight of the active compound. Other pharmacologically activesubstances can also be present, including other compounds of the presentinvention. The pharmaceutical compositions of the invention can beprepared by any of the well known techniques of pharmacy, consistingessentially of admixing the components.

[0254] These compounds can be administered by any conventional meansavailable for use in conjunction with pharmaceuticals, either asindividual therapeutic compounds or as a combination of therapeuticcompounds.

[0255] The amount of compound which is required to achieve the desiredbiological effect will, of course, depend on a number of factors such asthe specific compound chosen, the use for which it is intended, the modeof administration, and the clinical condition of the recipient.

[0256] In general, a daily dose can be in the range of from about 0.3 toabout 100 mg/kg bodyweight/day, preferably from about 1 mg to about 50mg/kg bodyweight/day, more preferably from about 3 to about 10 mg/kgbodyweight/day. This total daily dose can be administered to the patientin a single dose, or in proportionate multiple subdoses. Subdoses can beadministered 2 to 6 times per day. Doses can be in sustained releaseform effective to obtain desired results.

[0257] Orally administrable unit dose formulations, such as tablets orcapsules, can contain, for example, from about 0.1 to about 100 mg ofbenzothiepine compound, preferably about 1 to about 75 mg of compound,more preferably from about 10 to about 50 mg of compound. In the case ofpharmaceutically acceptable salts, the weights indicated above refer tothe weight of the benzothiepine ion derived from the salt.

[0258] Oral delivery of an ileal bile acid transport inhibitor of thepresent invention can include formulations, as are well known in theart, to provide prolonged or sustained delivery of the drug to thegastrointestinal tract by any number of mechanisms. These include, butare not limited to, pH sensitive release from the dosage form based onthe changing pH of the small intestine, slow erosion of a tablet orcapsule, retention in the stomach based on the physical properties ofthe formulation, bioadhesion of the dosage form to the mucosal lining ofthe intestinal tract, or enzymatic release of the active drug from thedosage form. The intended effect is to extend the time period over whichthe active drug molecule is delivered to the site of action (the ileum)by manipulation of the dosage form. Thus, enteric-coated andenteric-coated controlled release formulations are within the scope ofthe present invention. Suitable enteric coatings include celluloseacetate phthalate, polyvinylacetate phthalate,hydroxypropylmethylcellulose phthalate and anionic polymers ofmethacrylic acid and methacrylic acid methyl ester.

[0259] When administered intravenously, the dose can, for example, be inthe range of from about 0.1 mg/kg body weight to about 1.0 mg/kg bodyweight, preferably from about 0.25 mg/kg body weight to about 0.75 mg/kgbody weight, more preferably from about 0.4 mg/kg body weight to about0.6 mg/kg body weight. This dose can be conveniently administered as aninfusion of from about 10 ng/kg body weight to about 100 ng/kg bodyweight per minute. Infusion fluids suitable for this purpose cancontain, for example, from about 0.1 ng to about 10 mg, preferably fromabout 1 ng to about 10 mg per milliliter. Unit doses can contain, forexample, from about 1 mg to about 10 g of the compound of the presentinvention. Thus, ampoules for injection can contain, for example, fromabout 1 mg to about 100 mg.

[0260] Pharmaceutical compositions according to the present inventioninclude those suitable for oral, rectal, topical, buccal (e.g.,sublingual), and parenteral (e.g., subcutaneous, intramuscular,intradermal, or intravenous) administration, although the most suitableroute in any given case will depend on the nature and severity of thecondition being treated and on the nature of the particular compoundwhich is being used. In most cases, the preferred route ofadministration is oral.

[0261] Pharmaceutical compositions suitable for oral administration canbe presented in discrete units, such as capsules, cachets, lozenges, ortablets, each containing a predetermined amount of at least one compoundof the present invention; as a powder or granules; as a solution or asuspension in an aqueous or non-aqueous liquid; or as an oil-in-water orwater-in-oil emulsion. As indicated, such compositions can be preparedby any suitable method of pharmacy which includes the step of bringinginto association the active compound(s) and the carrier (which canconstitute one or more accessory ingredients). In general, thecompositions are prepared by uniformly and intimately admixing theactive compound with a liquid or finely divided solid carrier, or both,and then, if necessary, shaping the product. For example, a tablet canbe prepared by compressing or molding a powder or granules of thecompound, optionally with one or more assessory ingredients. Compressedtablets can be prepared by compressing, in a suitable machine, thecompound in a free-flowing form, such as a powder or granules optionallymixed with a binder, lubricant, inert diluent and/or surfaceactive/dispersing agent(s). Molded tablets can be made by molding, in asuitable machine, the powdered compound moistened with an inert liquiddiluent.

[0262] Pharmaceutical compositions suitable for buccal (sub-lingual)administration include lozenges comprising a compound of the presentinvention in a flavored base, usually sucrose, and acacia or tragacanth,and pastilles comprising the compound in an inert base such as gelatinand glycerin or sucrose and acacia.

[0263] Pharmaceutical compositions suitable for parenteraladministration conveniently comprise sterile aqueous preparations of acompound of the present invention. These preparations are preferablyadministered intravenously, although administration can also be effectedby means of subcutaneous, intramuscular, or intradermal injection. Suchpreparations can conveniently be prepared by admixing the compound withwater and rendering the resulting solution sterile and isotonic with theblood. Injectable compositions according to the invention will generallycontain from 0.1 to 5% w/w of a compound disclosed herein.

[0264] Pharmaceutical compositions suitable for rectal administrationare preferably presented as unit-dose suppositories. These can beprepared by admixing a compound of the present invention with one ormore conventional solid carriers, for example, cocoa butter, and thenshaping the resulting mixture.

[0265] Pharmaceutical compositions suitable for topical application tothe skin preferably take the form of an ointment, cream, lotion, paste,gel, spray, aerosol, or oil. Carriers which can be used includevaseline, lanoline, polyethylene glycols, alcohols, and combinations oftwo or more thereof. The active compound is generally present at aconcentration of from 0.1 to 15% w/w of the composition, for example,from 0.5 to 2%.

[0266] Transdermal administration is also possible. Pharmaceuticalcompositions suitable for transdermal administration can be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time. Such patchessuitably contain a compound of the present invention in an optionallybuffered, aqueous solution, dissolved and/or dispersed in an adhesive,or dispersed in a polymer. A suitable concentration of the activecompound is about 1% to 35%, preferably about 3% to 15%. As oneparticular possibility, the compound can be delivered from the patch byelectrotransport or iontophoresis, for example, as described inPharmaceutical Research, 3(6), 318 (1986).

[0267] In any case, the amount of active ingredient that can be combinedwith carrier materials to produce a single dosage form to beadministered will vary depending upon the host treated and theparticular mode of administration.

[0268] The solid dosage forms for oral administration includingcapsules, tablets, pills, powders, and granules noted above comprise oneor more compounds of the present invention admixed with at least oneinert diluent such as sucrose, lactose, or starch. Such dosage forms mayalso comprise, as in normal practice, additional substances other thaninert diluents, e.g., lubricating agents such as magnesium stearate. Inthe case of capsules, tablets, and pills, the dosage forms may alsocomprise buffering agents. Tablets and pills can additionally beprepared with enteric coatings.

[0269] Liquid dosage forms for oral administration can includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art, such aswater. Such compositions may also comprise adjuvants, such as wettingagents, emulsifying and suspending agents, and sweetening, flavoring,and perfuming agents.

[0270] Injectable preparations, for example, sterile injectable aqueousor oleaginous suspensions may be formulated according to the known artusing suitable dispersing or setting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

[0271] Pharmaceutically acceptable carriers encompass all the foregoingand the like.

[0272] Treatment Regimen

[0273] The dosage regimen to prevent, give relief from, or ameliorate adisease condition having hyperlipemia as an element of the disease,e.g., atherosclerosis, or to protect against or treat further highcholesterol plasma or blood levels with the compounds and/orcompositions of the present invention is selected in accordance with avariety of factors. These include the type, age, weight, sex, diet, andmedical condition of the patient, the severity of the disease, the routeof administration, pharmacological considerations such as the activity,efficacy, pharmacokinetics and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized, andwhether the compound is administered as part of a drug combination.Thus, the dosage regimen actually employed may vary widely and thereforedeviate from the preferred dosage regimen set forth above.

[0274] Initial treatment of a patient suffering from a hyperlipidemiccondition can begin with the dosages indicated above. Treatment shouldgenerally be continued as necessary over a period of several weeks toseveral months or years until the hyperlipidemic disease condition hasbeen controlled or eliminated. Patients undergoing treatment with thecompounds or compositions disclosed herein can be routinely monitoredby, for example, measuring serum cholesterol levels by any of themethods well known in the art, to determine the effectiveness oftherapy. Continuous analysis of such data permits modification of thetreatment regimen during therapy so that optimal effective amounts ofcompounds of the present invention are administered at any point intime, and so that the duration of treatment can be determined as well.In this way, the treatment regimen/dosing schedule can be rationallymodified over the course of therapy so that the lowest amount of ilealbile acid transport inhibitor of the present invention which exhibitssatisfactory effectiveness is administered, and so that administrationis continued only so long as is necessary to successfully treat thehyperlipidemic condition.

[0275] The following non-limiting examples serve to illustrate variousaspects of the present invention.

EXAMPLES OF SYNTHETIC PROCEDURES

[0276] Preparation 1

[0277] 2-Ethyl-2-(mesyloxymethyl)hexanal (1)

[0278] To a cold (10° C.) solution of 12.6 g (0.11 mole) ofmethanesulfonyl chloride and 10.3 g (0.13 mole) of triethylamine wasadded dropwise 15.8 g of 2-ethyl-2-(hydroxymethyl)hexanal, preparedaccording to the procedure described in Chem. Ber. 98, 728-734 (1965),while maintaining the reaction temperature below 30° C. The reactionmixture was stirred at room temperature for 18 h, quenched with diluteHCl and extracted with methlyene chloride. The methylene chlorideextract was dried over MgSO₄ and concentrated in vacuo to give 24.4 g ofbrown oil.

[0279] Preparation 2

[0280] 2-((2-Benzoylphenylthio)methyl)-2-ethylhexanal (2)

[0281] A mixture of 31 g (0.144 moi) of 2-mercaptobenzophenone, preparedaccording to the procedure described in WO 93/16055, 24.4 g (0.1 mole)of 2-ethyl-2-(mesyloxymethyl)-hexanal (1), 14.8 g (0.146 mole) oftriethylamine, and 80 mL of 2-methoxyethyl ether was held at reflux for24 h. The reaction mixture was poured into 3N HCl and extracted with 300mL of methylene chloride. The methylene chloride layer was washed with300 mL of 10% NaOH, dried over MgSO₄ and concentrated in vacuo to remove2-methoxyethyl ether. The residue was purified by HPLC (10%EtOAc-hexane) to give 20.5 g (58%) of 2 as an oil.

EXAMPLE 1

[0282] 3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine (3),cis-3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepin-(5H)4-one (4a) andtrans-3-Butyl-3-ethyl-5-phenyl-2,3-dihydro-benzothiepin-(5H)4-one (4b)

[0283] A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole)of TiCl₃ and 80 mL of anhydrous ethylene glycol dimethyl ether (DME) washeld at reflux for 2 h. The reaction mixture was cooled to 5° C. To thereaction mixture was added dropwise a solution of 3.54 is g (0.01 mole)of 2 in 30 mL of DME in 40 min. The reaction mixture was stirred at roomtemperature for 16 h and then was held at reflux for 2 h and cooledbefore being poured into brine. The organic was extract into methylenechloride. The methylene chloride extract was dried over MgSO₄ andconcentrated in vacuo. The residue was purified by HPLC (hexane) to give1.7 g (43%) of 3 as an oil in the first fraction. The second fractionwas discarded and the third fraction was further purified by HPLC(hexane) to give 0.07 g (2%) of 4a in the earlier fraction and 0.1 g(3%) of 4b in the later fraction.

Example 2

[0284]cis-3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepin-(5H)4-one-1,1-dioxide(5a) andtrans-3-Butyl-3-ethyl-5-phenyl-2,3-dihydro-benzothiepin-(5H)4-one-1,1-dioxide(5b)

[0285] To a solution of 1.2 g (3.5 mmole) of 50-60% MCPBA in 20 mL ofmethylene chloride was added 0.59 g (1.75 mmole) of a mixture of 4a and4b in 10 mL of methylene chloride. The reaction mixture was stirred for20 h. An additional 1.2 g (1.75 mmole) of 50-60% MAPBA was added and thereaction mixture was stirred for an additional 3 h then was trituratedwith 50 mL of 10% NaOH. The insoluble solid was filtered. The methylenechloride layer of the filtrate was washed with brine, dried over MgSO₄,and concentrated in vacuo. The residual syrup was purified by HPLC (5%EtOAc-hexane) to give 0.2 g (30%)of 5a as an oil in the first fractionand 0.17 g (26%) of 5b as an oil in the second fraction.

Example 3

[0286] (3α,4α,5β)3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(6a), (3α, 4β,5α)3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(6b), (3α,4α,5α)3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(6c), and (3β,4β,5β)3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(6d)

[0287] A. Reduction of 5a and 5b with Sodium Borohydride

[0288] To a solution of 0.22 g (0.59 mmole) of 5b in 10 mL of ethanolwas added 0.24 g (6.4 mmole) of sodium borohydride. The reaction mixturewas stirred at room temperature for 18 h and concentrated in vacuo toremove ethanol. The residue was triturated with water and extracted withmethylene chloride. The methylene chloride extract was dried over MgSO₄and concentrated in vacuo to give 0.2 g of syrup. In a separateexperiment, 0.45 g of 5a was treated with 0.44 g of sodium borohydridein 10 mL of ethanol and was worked up as described above to give 0.5 gof syrup which was identical to the 0.2 g of syrup obtained above. Thesetwo materials were combined and purified by HPLC using 10% EtOAc-hexaneas eluant. The first fraction was 0.18 g (27%) of 6a as a syrup. Thesecond fraction was 0.2 g (30%) of 6b also as a syrup. The column wasthen eluted with 20% EtOAc-hexane to give 0.077 g (11%) of 6c in thethird fraction as a solid. Recrystallization from hexane gave a solid,mp 179-181° C. Finally, the column was eluted with 30% EtOAc-hexane togive 0.08 g (12%) of 6d in the fourth fraction as a solid.Recrystallization from hexane gave a solid, mp 160-161° C.

[0289] B. Conversion of 6a to 6c and 6d with NaOH and PTC

[0290] To a solution of 0.29 g (0.78 mmole) of 6a in 10 mL CH₂Cl₂ , wasadded 9 g of 40% NaOH. The reaction mixture was stirred for 0.5 h atroom temperature and was added one drop of Aliquat-336(methyltricaprylylammonium chloride) phase transfer catalyst (PTC). Themixture was stirred for 0.5 h at room temperature before being treatedwith 25 mL of ice-crystals then was extracted with CH₂Cl₂ (3×10 ml),dried over MgSO4 and concentrated in vacuo to recover 0.17 g of acolorless film. The components of this mixture were separated using anHPLC and eluted with EtOAc-hexane to give 12.8 mg (4%) of2-(2-benzylphenylsulfonylmethyl)-2-ethylhexenal in the first fraction,30.9 mg (11%) of 6c in the second fraction and 90.0 mg (31%) of 6d inthe third fraction.

[0291] Oxidation of 6a to 5b

[0292] To a solution of 0.20 g (0.52 mmole) of 6a in 5 mL of CH₂C1₂ wasadded 0.23 g (1.0 mmole) of pyridinium chlorochromate. The reactionmixture was stirred for 2 h then was treated with additional 0.23 g ofpyridinium chlorochromate and stirred overnight. The dark reactionmixture was poured into a ceramic filterfrit containing silica gel andwas eluted with CH₂Cl₂. The filtrate was concentrated in vacuo torecover 167 mg (87%) of 5b as a colorless oil.

EXAMPLE 4

[0293] 3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine-1,1-dioxide (7)

[0294] To a solution of 5.13 g (15.9 rnmole) of 3 in 50 mL of CH₂Cl₂ wasadded 10 g (31.9 mmole) of 50-60% MCPBA (m-chloroperoxybenzoic acid)portionwise causing a mild reflux and formation of a white solid. Thereaction mixture was allowed to stir overnight under N₂ and wastriturated with 25 mL of water followed by 50 mL of 10% NaOH solution.The organic was extracted into CH₂Cl₂ (4×20 mL) . The CH₂Cl₂ extract wasdried over MgSO₄ and evaporated to dryness to recover 4.9 g (87%) of anopaque viscous oil.

EXAMPLE 5

[0295] (1aα,2β,8b═)2-Butyl-2-ethyl-8b-phenyl-1α,2,3,8b-tetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide(8a) (1aα,2α,8bα)2-Butyl-2-ethyl-8b-phenyl-1a,2,3,8b-tetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide(8b)

[0296] To 1.3 g (4.03 mole) of 3 in 25 mL of CHCl₃ was added portionwise5 g (14.1 mmole) of 50-60% MCPBA causing a mild exotherm. The reactionmixture was stirred under N₂ overnight and was then held at reflux for 3h. The insoluble white slurry was filtered. The filtrate was extractedwith 10% potassium carbonate (3×50 mL), once with brine, dried overMgSO₄, and concentrated in vacuo to give 1.37 g of a light yellow oil.Purification by HPLC gave 0.65 g of crystalline product. This product isa mixture of two isomers. Trituration of this crystalline product inhexane recovered 141.7 mg (10%) of a white crystalline product. Thisisomer was characterized by NMR and mass spectra to be the (1aα,2β,8bα)isomer 8a. The hexane filtrate was concentrated in vacuo to give 206 mgof white film which is a mixture of 30% 8a and 70% 8b by ¹H NMR.

EXAMPLE 6

[0297]cis-3-Butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide(9a),trans-3-Butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(9b), and3-Butyl-3-ethyl-4-hydroxy-5-cyclohexylidine-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(10)

[0298] A mixture of 0.15 g (0.4 mmole) of a 3:7 mixture of 8a and Bb wasdissolved in 15 ml MeOH in a 3 oz. Fisher/Porter vessel, then was added0.1 g of 10% Pd/C catalyst. This mixture was hydrogenated at 70 psi H₂for 5 h and filtered. The filtrate was evaporated to dryness in vacuo torecover 0.117 g of a colorless oil. This material was purified by HPLCeluting with EtOAc-hexane. The first fraction was 4.2 mg (3%) of 9b. Thesecond fraction, 5.0 mg (4%), was a 50/50 mixture of 9a and 9b. Thethird fraction was 8.8 mg (6%) of 6a . The fourth fraction was 25.5 mg(18%) of 6b. The fifth fraction was 9.6 mg (7%) of a mixture of 6b and aproduct believed to be3-butyl-3-ethyl-4,5-dihydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxidebased on mass spectrum. The sixth fraction was 7.5 mg (5%) of a mixtureof 6d and one of the isomers of 10, 10a.

EXAMPLE 7

[0299] In another experiment, a product (3.7 g) from epoxidation of 3with excess MCPBA in refluxing CHCl₃ under air was hydrogenated in 100mL of methanol using 1 g of 10% Pd/C catalyst and 70 psi hydrogen. Theproduct was purified by HPLC to give 0.9 g (25%) of 9b, 0.45 g (13%) of9a, 0.27 g (7%) of 6a, 0.51 g (14%) of 6b, 0.02 g (1%) of 6c, 0.06 g(2%) of one isomer of 10, 10a and 0.03 g (1%) of another isomer of 10,10b.

EXAMPLE 8

[0300] 2-((2-Benzoylphenylthio)methyl)butyraldehyde (11)

[0301] To an ice bath cooled solution of 9.76 g (0.116 mole of2-ethylacrolein in 40 mL of dry THF was added 24.6 g (0.116 mole) of2-mercaptobenzophenone in 40 mL of THF followed by 13 g (0.128 mole) oftriethylamine. The reaction mixture was stirred at room temperature for3 days , diluted with ether, and was washed successively with diluteHCl, brine, and 1 M potassium carbonate. The ether layer was dried overMgSO₄ and concentrated in vacuo. The residue was purified by HPLC (10%EtOAc-hexane) to give 22 g (64%) of 11 in the second fraction. Anattempt to further purifiy this material by kugelrohr distillation at0.5 torr (160-190° C.) gave a fraction (12.2 g) which contained startingmaterial indicating a reversed reaction during distillation. Thismaterial was dissolved in ether (100 mL) and was washed with 50 mL of 1M potassium carbonate three times to give 6.0 g of a syrup which waspurified by HPLC (10% EtOAc-hexane) to give 5.6 g of pure 11.

EXAMPLE 9

[0302] 3-Ethyl-5-phenyl-2,3-dihydrobenzothiepine (12)

[0303] To a mixture of 2.61 g (0.04 mole) of zinc dust and 60 mL of DMEwas added 7.5 g (0.048 mole) of TiCl₃. The reaction mixture was held atreflux for 2 h. A solution of 2.98 g (0.01 mole) of 11 was addeddropwise in 1 h. The reaction mixture was held at reflux for 18 h,cooled and poured into water. The organic was extracted into ether. Theether layer was washed with brine and filtered through Celite. Thefiltrate was dried over MgSO₄ and concentrated. The residual oil (2.5 g)was purified by HPLC to give 2.06 g (77%) of 12 as an oil in the secondfraction.

EXAMPLE 10

[0304] (1aα,2α,8bα)2-Ethyl-8b-phenyl-1a,2,3,8b-tetrahydro-benzothiepino-[4,5-b]oxirene-4,4-dioxide(13)

[0305] To a solution of 1.5 g (5.64 mmole) of 12 in 25 ml of CHCl₃ wasadded 6.8 g (19.4 mmole) of 50-60% MCPB portionwise causing an exothemand formation of a white solid. The mixture was stirred at roomtemperature overnight diluted with 100 ml methylene chloride and washedsuccessively with 10% K₂CO₃ (4x50 ml), water (twice with 25 ml) andbrine. The organic layer was then dried over MgSO₄ and evaporated todryness to recover 1.47 g of an off white solid. ¹H NMR indicated thatonly one isomer is present. This solid was slurried in 200 ml of warmEt₂O and filtered to give 0.82 g (46%) of 13 as a white solid, mp185-186.5° C.

EXAMPLE 11

[0306] (3α,4β,5α)-3-Ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide(14a), (3α,4β,5β)3-Ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(14b), andcis-3-Ethyl-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (15)

[0307] A mixture of 0.5 g (1.6 mole) of 13, 50 ml of acetic acid and 0.5g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 4 h.The crude reaction slurry was filtered and the filtrate was stirred with150 ml of a saturated NaHCO₃ solution followed by 89 g of NaHCO₃ powderportionwise to neutralize the rest of acetic acid. The mixture wasextracted with methylene chloride (4×25 ml), then the organic layer wasdried over MgSO₄ and concentrated in vacuo to give 0.44 g (87%) of avoluminous white solid which was purified by HPLC (EtOAc-Hexane) to give26.8 mg (6%) of 15 in the first fraction, 272 mg (54%) of 14a as asolid, mp 142-143.5° C., in the second fraction, and 35 mg (7%) ofimpure 14b in the third fraction.

EXAMPLE 12

[0308] 2-Ethyl-2-((2-Hydroxymethylphenyl)thiomethyl)hexenal (16)

[0309] A mixture of 5.0 g (0.036 mole) of 2-mercaptobenzyl alcohol, 6.4g (0.032 mole) of 1, 3.6 g (0.036 mole) of triethylamine and 25 mL of2-methoxyethyl ether was held at reflux for 7 h. Additional 1.1 g ofmercaptobenzyl alcohol and 0.72 g of triethylamine was added to thereaction mixture and the mixture was held at reflux for additional 16 h.The reaction mixture was cooled and poured into 6N HCl and extractedwith methylene chloride. The methylene chloride extract was washed twicewith 10% NaOH, dried over MgSO₄ and concentrated in vacuo to give 9.6 gof residue. Purification by HPLC (20% EtOAc-hexane) gave 3.7 g (41%)of16 as an oil.

EXAMPLE 13

[0310] 2-Ethyl-2-((2-formylphenyl)thiomethyl)hexenal (17)

[0311] A mixture of 3.7 g of 16, 5.6 g (0.026 mole) of pyridiniumchlorochromate, 2 g of Celite and 30 mL of methylene chloride wasstirred for 18 h and filtered through a bed of silica gel. The silicagel was eluted with methylene chloride. The combined methylene chlorideeluant was purified by HPLC (20% ETOAc-hexane) to give 2.4 g (66%) of anoil.

EXAMPLE 14

[0312] 3-Butyl-3-ethyl-2,3-dihydrobenzothiepine (18)

[0313] A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole)of TiCl₃, and 50 mL of DME was held at reflux for 2 h and cooled to roomtemperature. To this mixture was added 2.4 g (8.6 mmole) of 17 in 20 mLof DME in 10 min. The reaction mixture was stirred at room temperaturefor 2 h and held at reflux for 1 h then was let standing at roomtemperature over weekend. The reaction mixture was poured into diluteHCl and was stirred with methylene chloride. The methylenechloride-water mixture was filtered through Celite. The methylenechloride layer was washed with brine, dried over MgSO₄, and concentratedin vacuo to give 3.0 g of a residue. Purification by HPLC gave 0.41 g(20%) of 18 as an oil in the early fraction.

EXAMPLE 15

[0314] (1aα,2α,8bα )2-Butyl-2-ethyl-1a,2,3,8b-tetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide(19a) and (1aα,2β,8bα)2-Butyl-2-ethyl-8b-phenyl-1a,2,3,8b-tetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide(19b)

[0315] To a solution of 0.4 g of 0.4 g (1.6 mmole) of 18 in 30 mL ofmethylene chloride was added 2.2 g (3.2 mmole) of 50-60% MCPBA. Thereaction mixture was stirred for 2 h and concentrated in vacuo. Theresidue was dissolved in 30 mL of CHCl₃ and was held at reflux for 18 hunder N₂. The reaction mixture was stirred with 100 mL of 10% NaOH and 5g of sodium sulfite. The methylene chloride layer was washed with brine,dried over MgSO₄ and concentrated in vacuo. The residue was purified byHPLC (20% EtOAc-hexane) to give a third fraction which was furtherpurified by HPLC (10% EtOAc-hexane) to give 0.12 g of syrup in the firstfraction. Recrystallization from hexane gave 0.08 g (17%) of 19a, mp89.5-105.5° C. The mother liquor from the first fraction was combinedwith the second fraction and was further purified by HPLC to giveadditional 19a in the first fraction and 60 mg of 19b in the secondfraction. Crystallization from hexane gave 56 mg of a white solid.

EXAMPLE 16

[0316] 3-Butyl-3-ethyl-4,5-dihydroxy-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (20)

[0317] This product was isolated along with 6b from hydrogenation of amixture of 8a and 8b.

EXAMPLE 17

[0318]3-Butyl-3-ethyl-4-hydroxy-5-phenylthio-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide(21)

[0319] A mixture of 25 mg (0.085 mmole) of 19b, 0.27 g (2.7 mmole) ofthiophenol, 0.37 g (2.7 mmole) of potassium carbonate, and 4 mL of DMFwas stirred at room temperature under N₂ for 19 h. The reaction mixturewas poured into water and extracted with methylene chloride. Themethylene chloride layer was washed successively with 10% NaOH andbrine, dried over MgSO₄, and concentrated in vacuo to give 0.19 g ofsemisolid which contain substantial amounts of diphenyl disulfide. Thismaterial was purified by HPLC (5% EtOAc-hexane) to remove diphenyldisulfide in the first fraction. The column was then eluted with 20%EtOAc-hexane to give 17 mg of a first fraction, 4 mg of a secondfraction and 11 mg of a third fraction which were three differentisomers of 21, i.e. 21a, 21b, and 21c, respectively, by ¹H NMR and massspectra.

EXAMPLE 18

[0320] Alternative Synthesis of 6c and 6d

[0321] A. Preparation from2-((2-Benzoylphenylthio)methyl)-2-ethylhexanal (2)

[0322] Step 1. 2-((2-Benzoylphenylsulfonyl)methyl)-2-ethylhexanal (44)

[0323] To a solution of 9.0 g (0.025 mole) of compound 2 in 100 ml ofmethylene chloride was added 14.6 g (0.025 mol) of 50-60% MCPBAportionwise. The reaction mixture was stirred at room temperature for 64h then was stirred with 200 ml of 1 M potassium carbonate and filteredthrough Celite. The methylene chloride layer was washed twice with 300ml of 1 M potassium carbonate, once with 10% sodium hydroxide and oncewith brine. The insoluble solid formed during washing was removed byfiltration through Celite. The methylene chloride solution was dried andconcentrated in vacuo to give 9.2 g (95%)of semisolid. A portion (2.6 g)of this solid was purified by HPLC(10% ethyl acetate-hexane) to give 1.9g of crystals, mp 135-136° C.

[0324] Step 2. 2-((2-Benzylphenylsulfonyl)methyl)-2-ethylhexanal (45)

[0325] A solution of 50 g (0.13 mole) of crude 44 in 250 ml of methylenechloride was divided in two portions and charged to two Fisher-Porterbottles. To each bottle was charged 125 ml of methanol and 5 g of 10%Pd/C. The bottles were pressurized with 70 psi of hydrogen and thereaction mixture was stirred at room temperature for 7 h before beingcharged with an additional 5 g of 10% Pd/C. The reaction mixture wasagain hydrogenated with 70 psi of hydrogen for 7 h. This procedure wasrepeated one more time but only 1 g of Pd/C was charged to the reactionmixture. The combined reaction mixture was filtered and concentrated invacuo to give 46.8 g of 45 as brown oil.

[0326] Step 3. (3α,4α,5α)3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(6c), and (3a,4p,5S)3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(6d)

[0327] To a solution of 27.3 g (73.4 mmole) of 45 in 300 ml of anhydrousTHF cooled to 2° C. with an ice bath was added 9.7 g (73.4 mmole) of 95%potassium t-butoxide. The reaction mixture was stirred for 20 min,quenched with 300 ml of 10% HCl and extracted with methylene chloride.The methylene chloride layer was dried over magnesium sulfate andconcentrated in vacuo to give 24.7 g of yellow oil. Purification by HPLC(ethyl acetate-hexane) yielded 9.4 g of recovered 45 in the firstfraction, 5.5 g (20%) of 6c in the second fraction and 6.5 g (24%) of 6din the third fraction.

[0328] B. Preparation from 2-hydroxydiphenylmethane

[0329] Step 1. 2-mercaptodiphenylmethane (46)

[0330] To a 500 ml flask was charged 16 g (0.33 mol) of 60% sodiumhydride oil dispersion. The sodium hydride was washed twice with 50 mlof hexane. To the reaction flask was charged 100 ml of DMF. To thismixture was added a solution of 55.2 g (0.3 mol) of2-hydroxydiphenylmethane in 200 ml of DMF in 1 h while temperature wasmaintained below 30° C. by an ice-water bath. After complete addition ofthe reagent, the mixture was stirred at room temperature for 30 min thencooled with an ice bath. To the reaction mixture was added 49.4 g (0.4mole) of dimethyl thiocarbamoyl chloride at once. The ice bath wasremoved and the reaction mixture was stirred at room temperature for 18h before being poured into 300 ml of water. The organic was extractedinto 500 ml of toluene. The toluene layer was washed successively with10% sodium hydroxide and brine and was concentrated in vacuo to give78.6 g of a yellow oil which was 95% pure dimethyl O -2-benzylphenylthiocarbamate. This oil was heated at 280-300° C. in a kugelrohhr potunder house vacuum for 30 min. The residue was kugelrohr distilled at 1torr (180-280° C.). The distillate (56.3 g) was crystallized frommethanol to give 37.3 g (46%) of the rearranged product dimethylS-2-benzylphenyl thiocarbamate as a yellow solid. A mixture of 57 g(0.21 mole) of this yellow solid, 30 g of potassium hydroxide and 150 mlof methanol was stirred overnight then was concentrated in vacuo. Theresidue was diluted with 200 ml of water and extracted with ether. Theaqueous layer was made acidic with concentrate HCl, The oily suspensionwas extracted into ether. The ether extract was dried over magnesiumsulfate and concentrated in vacuo. The residue was crystallized fromhexane to give 37.1 g (88%) of 2-mercaptodiphenylmethane as a yellowsolid.

[0331] Step 2. 2-((2-Benzylphenylthio)methyl)-2-ethylhexanal (47)

[0332] A mixture of 60 g (03 mole) of yellow solid from step 1, 70 g(0.3 mole) of compound 1 from preparation 1, 32.4 g (0.32 mole) oftriethylamine, 120 ml of 2-methoxyethyl ether was held at reflux for 6hr and concentrated in vacuo. The residue was triturated with 500 ml ofwater and 30 ml of concentrate HCl. The organic was extracted into 400ml of ether. The ether layer was washed successively with brine, 10%sodium hydroxide and brine and was dried over magnesium sulfate andconcentrated in vacuo. The residue (98.3 g) was purified by HPLC with2-5% ethyl acetate-hexane as eluent to give2-((2-benzylphenylthio)methyl)-2-ethylhexanal 47 as a yellow syrup.

[0333] Step 3. 2-((2-Benzylphenylsulfonyl)rmethyl)-2-ethylhexanal (45)

[0334] To a solution of 72.8 g (0.21 mole) of yellow syrup from step 2in 1 liter of methylene chloride cooled to 10° C. was added 132 g of50-60% MCPBA in 40 min. The reaction mixture was stirred for 2 h. Anadditional 13 g of 50-60% MCPBA was added to the reaction mixture. Thereaction mixture was stirred for 2 h and filtered through Celite. Themethylene chloride solution was washed twice with 1 liter of 1 Mpotassium carbonate then with 1 liter of brine. The methylene chloridelayer was dried over magnesium sulfate and concentrated to 76 g of2-((2-benzylphenylsulfonyl)methyl)-2-ethylhexanal 45 as a syrup.

[0335] Step 4. (3α, 4α, 5α)3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide(6c), and (3a,40,5p)3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(6d) Reaction of 45 with potassium t-butoxide according to the procedurein step 3 of procedure A gave pure 6c and 6d after HPLC.

EXAMPLE 19

[0336] (3α,4β,5β)3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(25) and (3a, 4a, 5a)3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(26)

[0337] Step 1. Preparation of 2-((2-benzoyl-4-methoxyphenylthio)methyl)-2-ethylhexanal (22)

[0338] 2-Hydroxy-4-methoxybenzophenone was converted to the dimethylO-2-benzoyphenyl thiocarbamate by methods previously described inexample 18. The product can be isolated by recrystallization fromethanol. Using this improved isolation procedure no chromatography wasneeded. The thermal rearrangement was performed by reacting thethiocarbamate( 5 g) in diphenyl ether at 260° C. as previouslydescribed. The improved isolation procedure which avoided achromatography step was described below.

[0339] The crude pyrolysis product was then heated at 65° C. in 100 mlof methanol and 100 ml of THF in the presence of 3.5 g of KOH for 4 h.After removing THF and methanol by rotary evaporation the solution wasextracted with 5% NaOH and ether. The base layer was acidified andextracted with ether to obtain a 2.9 g of crude thiophenol product. Theproduct was further purified by titrating the desired mercaptan intobase with limited KOH. After acidification and extraction with etherpure

[0340] 2-mercapto-4-methoxybenzophenone (2.3 g) was isolated.2-mercapto-4-methoxybenzophenone can readily be converted to the2-((2-benzoyl-4-methoxyphenylthio)methyl)-2-ethylhexanal (22) byreaction with 2-ethyl-2-(mesyloxymethyl)hexanal (1) as previouslydescribed.

[0341] Step 2.2-((2-Benzoyl-5-methoxyphenylsulfonyl)methyl)-2-ethylhexanal (23)

[0342] Substrate 22 was readily oxidized to2-((2-benzoyl-5-methoxyphenyl-sulfonyl)methyl) -2-ethyihexanal (23) asdescribed in example 18.

[0343] Step 3. 2- ((2-benzyl-5-methoxyphenylsulfonyl) methyl)-2-ethyihexanal (24)

[0344] Sulfone 23 was then reduced to2-((2-benzyl-5-methoxyphenyl-sulfonyl)methyl)-2-ethylhexanal (24) asdescribed in example 18.

[0345] Step 4. (3α,4β,5β)3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(25) and (3α,4α,5α)3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(26)

[0346] A 3-neck flask equipped with a powder additionfunnel,thermocouple and nitrogen bubbler was charged with 19.8 g (0.05mole) of sulfone 24 in 100 ml dry THF. The reaction was cooled to −1.6°C. internal temperature by means of ice/salt bath. Slowly add 5.61 g(0.05 mole) of potassium t-butoxide by means of the powder additionfunnel. The resulting light yellow solution was maintained at −1.6° C.After 30 min reaction 400 ml of cold ether was added and this solutionwas extracted with cold 10% HCl. The acid layer was extracted with 300ml of methylene chloride. The organic layers were combined and driedover magnesium sulfate and after filtration stripped to dryness toobtain 19.9 g of product. ¹H nmr and glpc indicated a 96% conversion toa 50/50 mixture of 25 and 26. The only other observable compound was 4%starting sulfone 24.

[0347] The product was then dissolved in 250 ml of 90/10 hexane/ethylacetate by warming to 50° C. The solution was allowed to cool to roomtemperature and in this way pure 26 can be isolated. The crystallizationcan be enhanced by addition of a seed crystal of 26. After 2crystallizations the mother liquor which was now 85.4% 25 and has a dryweight of 8.7 g. This material was dissolved in 100 ml of 90/10hexane/ethyl acetate and 10 ml of pure ethyl acetate at 40 C. Pure 25can be isolated by seeding this solution with a seed crystal of 25 afterstoring it overnight at 0 c.

EXAMPLE 25

[0348] (3α,4α,5α)3-Butyl-3-ethyl-4,8-dihydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide(27)

[0349] In a 25 ml round bottomed flask, 1 g of 26( 2.5 mmoles) and 10 mlmethylene chloride were cooled to −78° C. with stirring. Next 0.7 ml ofboron tribromide(7.5 mmole) was added via syringe. The reaction wasallowed to slowly warm to room temperature and stirred for 6 h. Thereaction was then diluted with 50 ml methylene chloride and washed withsaturated NaCl and then water.The organic layer was dried over magnesiumsulfate. The product (0.88 g) 27 was characterized by NMR and massspectra.

EXAMPLE 21

[0350] General Alkylation of phenol 27

[0351] A 25 ml flask was charged with 0.15 g of 27(0.38 mmole), 5 mlanhydrous DMF, 54 mg of potassium carbonate(0.38 mmole) and 140 mg ethyliodide (0.9 mmole). The reaction was stirred at room temperatureovernight.The reaction was diluted with 50 ml ethyl ether and washedwith water (25 ml) then 5% NaOH (20 ml) and then sat. NaCl. Afterstripping off the solvent the ethoxylated product 28 was obtained inhigh yield. The product was characterized by NMR and mass spectra. Thissame procedure was used to prepare products listed in table 1 from thecorresponding iodides or bromides. For higher boiling alkyl iodides andbromides only one equivalent of the alkyl halide was used. TABLE 1

Formula for Table 1 Compound No. R 27 H 26 Me 28 Et 29 hexyl 30 Ac 31(CH2) 6-N-pthalimide

EXAMPLE 22

[0352] (3α,4α,5α)3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(37) and (3α,4β,5β)3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(38)

[0353] Step 1. Preparation of 2-chloro-5-nitrodiphenylmethane (32)

[0354] Procedure adapted from reference :Synthesis -Stuttgart 9 770-772(1986) Olah G. Et al

[0355] Under nitrogen, a 3 neck flask was charged with 45 g (0.172 mole) of 2-chloro-5-nitrobenzophenone in 345 ml methylene chloride and thesolution was cooled to ice/water temperature. By means of an additionalfunnel, 150 g( 0.172 mole) of trifluoromethane sulfonic acid in 345 mlmethylene chloride was added slowly. Next 30 g of triethylsilane (0.172mole) in 345 ml methylene chloride was added dropwise to the chilledsolution. Both addition steps( trifluoromethane sulfonic acid andtriethylsilane)were repeated. After the additions were completed thereaction was allowed to slowly warm up to room temperature and stirredfor 12 h under nitrogen. The reaction mixture was then poured into achilled stirred solution of 1600 ml of saturated sodium bicarbonate. Gasevolution occurred. Poured into a 4 liter separatory funnel andseparated layers. The methylene chloride layer was isolated and combinedwith two 500 ml methylene chloride extractions of the aqueous layer. Themethylene chloride solution was dried over magnesium sulfate andconcentrated in vacuo. The residue was recrystallized from hexane togive 39 g product. Structure 32 was confirmed by mass spectra and protonand carbon NMR.

[0356] Step 2. Preparation of2-((2-benzyl-4-nitrophenylthio)methyl)-2-ethylhexanal (33)

[0357] The 2-chloro-5-nitrodiphenylmethane product 32 (40 g, 0.156 mole)from above was placed in a 2 liter 2 neck flask with water condenser.Next 150 ml DMSO and 7.18 g (0.156 mole) of lithium sulfide was addedand the solution was stirred at 75° C. for 12 h. The reaction was cooledto room temperature and then 51.7 g of mesylate IV was added in 90 mlDMSO. The reaction mixture was heated to 80° C. under nitrogen. After 12h monitored by TLC and added more mysylate if necessary.

[0358] Continued the reaction until the reaction was completed. Next thereaction mixture was slowly poured into a 1900 ml of 5% acetic aqueoussolution with stirring, extracted with 4×700 ml of ether, and dried overMgSO₄. After removal of ether, 82.7 g of product was isolated. Thematerial can be further purified by silica gel chromatography using 95%hexane and 5% ethyl acetate. If pure mysylate was used in this stepthere was no need for further purification. The product 33 wascharacterized by mass spectra and NMR.

[0359] Step 3. Oxidation of the nitro product 33 to the sulfone2-((2-benzyl-4-nitrophenylsulfonyl)methyl)-2-ethylhexanal (34)

[0360] The procedure used to oxidize the sulfide 33 to the sulfone 34has been previously described.

[0361] Step 4. Reduction of 34 to2-((2-benzyl-4-hydroxyaminophenylsulfonyl)methyl)-2-ethylhexanal (35)

[0362] A 15 g sample of 34 was dissolved in 230 ml of ethanol and placedin a 500 ml rb flask under nitrogen. Next 1.5 g of 10 wt. % Pd/C wasadded and hydrogen gas was bubbled through the solution at roomtemperature until the nitro substrate 34 was consumed. The reactioncould be readily monitored by silica gel TLC using 80/20 hexane/EtOAc.Product 35 was isolated by filtering off the Pd/C and then stripping offthe EtOH solvent. The product was characterized by NMR and mass spectra.

[0363] Step 5. Preparation of the2-((2-benzyl-4-N,O-di-(t-butoxy-carbonyl)hydroxyaminophenylsulfonyl)methyl)-2-ethylhexanal(36).

[0364] A 13.35 g sample of 35 (0.0344 mole) in 40 ml of dry THF wasstirred in a 250 ml round bottomed flask. Next added 7.52 g (0.0344mole) of di-t-butyl dicarbonate in 7 ml THF. Heated at 60° C. overnight.Striped off THF and redissolved in methylene chloride. Extracted with 1%HCl; and then 5% sodium bicarbonate.

[0365] The product was further purified by column chromatography using90/10 hexane/ethyl acetate and then 70/30 hexane/ethyl acetate. Theproduct 36 was obtained (4.12 g) which appeared to be mainly thedi-(t-butoxycarbonyl) derivatives by proton NMR.

[0366] Step 6. (3α,4α,5α)3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (37) and (3α,4β,5β)3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(38)

[0367] A 250 ml 3-neck round bottomed flask was charged with 4 g of 36(6.8 mmoles), and 100 ml of anhydrous THF and cooled to −78° C. under anitrogen atmosphere. Slowly add 2.29 g potassium tert-butoxide(20.4mmoles) with stirring and maintaining a −78° C. reaction temperature.After 1 h at −78° C. the addition of base was completed and thetemperature was brought to −10° C. by means of a ice/salt bath. After 3h at −10° C., only trace 36 remained by TLC. Next add 35 ml of deionizedwater to the reaction mixture at −10° C. and stirred for 5 min. Stripedoff most of the THF and added to separatory funnel and extracted withether until all of the organic was removed from the water phase. Thecombined ether phases were washed with saturated NaCl and then driedover sodium sulfate. The only products by TLC and NMR were the two BOCprotected isomers of 37 and 38. The isomers were separated by silica gelchromatography using 85% hexane and 15% ethyl acetate; BOC-37 (0.71 g)and BOC- 38 (0.78 g).

[0368] Next the BOC protecting group was removed by reacting 0.87 g ofBOC-38 (1.78 mmoles) with 8.7 ml of 4 M HCl (34.8 mmoles)in dioxane for30 min. Next added 4.74 g of sodium acetate (34.8 mmoles) to thereaction mixture and 16.5 ml ether and stirred until clear. Aftertransferring to a separatory funnel extracted with ether and water andthen dried the ether layer with sodium sulfate. After removing theether, 0.665 g of 38 was isolated. Isomer 37 could be obtained in asimilar procedure.

EXAMPLE 23

[0369] (3α,4α,5α)3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(40) and (3α,4β,5β)3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(41)

[0370] Step 1.2-((2-Benzyl-4-(n-hexylamino)phenylsulfonyl)methyl)-2-ethylhexanal (39)

[0371] In a Fischer porter bottle weighed out 0.5 g of 34 (1.2 mmoles)and dissolved in 3.8 ml of ethanol under nitrogen. Next added 0.1 g ofPd/C and 3.8 ml of hexanal. Seal and pressure to 50 psi of hydrogen gas.Stirred for 48 h. After filtering off the catalyst and removing thesolvent by rotary evaporation 39 was isolated by column chromatography(0.16 g) using 90/10 hexane ethyl acetate and gradually increasing themobile phase to 70/30 hexane/ethyl acetate. The product wascharacterized by NMR and mass spectra.

[0372] Step 2. (3α,4α,5α)3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(40) and (3α,4β,5β)3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(41)

[0373] A 2-neck, 25 ml round bottomed flask with stir bar was chargedwith 0.158 g 39 (0.335 mmole) and 5 ml anhydrous THF under nitrogen.Cool to −10° C. by means of a salt/water bath. Slowly add 0.113 g ofpotassium tert butoxide (0.335 mmole) . After 15 min at −10° C. all ofthe starting material was consumed by TLC and only the two isomers 40and 41 were observed. Next added 5 ml of chilled 10% HCl and stirred at−10° C. for 5 min. Transferred to a separatory funnel and extract withether. Dried over sodium sulfate. Proton NMR of the dried product (0.143g) indicated only the presence of the two isomers 40 and 41. The twoisomers were separated by silica gel chromatography using 90/10 hexaneethyl acetate and gradually increasing the mobile phase to 70/30hexane/ethyl acetate. 40 ( 53.2 mg); 41(58.9 mg).

EXAMPLE 24

[0374] Quaternization of amine substrates 40 and 41

[0375] Amine products such as 40 and 41 can be readily alkylated toquaternary salts by reaction with alkyl halides. For example 40 in DMFwith 5 equivalents of methyl iodide in the presence of 2,6 dimethyllutidine produces the dimethylhexylamino quaternary salt.

EXAMPLE 25

[0376] (3α,4β,5β)3-Butyl-3-ethyl-4-hydroxy-5-(4-iodophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(42)

[0377] In a 25 ml round bottomed flask 0.5 g (1.3 mmole) of 6d , 0.67 gof mercuric triflate were dissolved in 20 ml of dry methylene chloridewith stirring. Next 0.34 g of Iodine was added and the solution wasstirred at room temperature for 30 h. The reaction was then diluted with50 ml methylene chloride and washed with 10 ml of 1 M sodiumthiosulfate; 10 ml of saturated KI ; and dried over sodium sulfate. SeeTetrahedron, Vol.50, No. 17, pp 5139-5146 (1994) Bachki, F. Et al.Massspectrum indicated a mixture of 6d , mono iodide 42 and a diiodideadduct. The mixture was separated by column chromatography and 42 wascharacterized bt NMR and mass spectra.

EXAMPLE 26

[0378] (3α,4β,5β)3-Butyl-5-(4-carbomethoxyphenyl)-3-ethyl-4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(43)

[0379] A 0.1 g sample of 42 ( 0.212 mmole), 2.5 ml dry methanol, 38 pltriethylamine (0.275 mmole) , 0.3 ml toluene and 37 mg of palladiumchloride (0.21 mmole) was charged to a glass lined mini reactor at 300psi carbon monoxide. The reaction was heated at 100° C. overnight. Thecatalyst was filtered and a high yield of product was isolated. Theproduct was characterized by NMR and mass spectra.

[0380] Note the ester functionalized product 43 can be converted to thefree acid by hydrolysis.

EXAMPLE 27

[0381] (3α,4α,5α)3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(48), and (3a,4D,50) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (49)

[0382] Step 1. 2-Mercapto-5-methoxybenzophenone (50)

[0383] Reaction of 66.2 g of 4-methoxythiophenol with 360 ml of 2.5 Nn-butyllithium, 105 g of tetramethylethylenediamine and 66.7 g ofbenzonitrile in 600 ml cyclohexane according to the procedure in WO93/16055 gave 73.2 g of brown oil which was kugelrohr distilled toremove 4-methoxythiophenol and gave 43.86 g of crude 50 in the potresidue.

[0384] Step 2. 2-((2-Benzoyl-4-methoxyphenylthio)methyl)-2-ethylhexanal(51)

[0385] Reaction of 10 g (0.04 mole) of crude 50 with 4.8 g (0.02 mole)ofmesylate 1 and 3.2 ml (0.23 mole) of triethylamine in 50 ml of diglymeaccording to the procedure for the preparation of 2 gave 10.5 g of crudeproduct which was purified by HPLC (5% ethyl acetate-hexane) to give 1.7g (22%) of 51.

[0386] Step 3.2-((2-Benzoyl-4-methoxyphenylsulfonyl)methyl)-2-ethyl-hexanal (52)

[0387] A solution of 1.2 g (3.1 mmoles) of 51 in 25 ml of methylenechloride was reacted with 2.0 g (6.2 mmoles) of 50-60% MCPBA accordingto the procedure of step 2 of procedure A in example 18 gave 1.16 g(90%) of 52 as a yellow oil.

[0388] Step 4.2-((2-Benzyl-4-methoxyphenylsulfonyl)methyl)-2-ethylhexanal (53)

[0389] Hydrogenation of 1.1 g of 52 according to the procedure of step 3of procedure A of example 18 gave 53 as a yellow oil (1.1 g).

[0390] Step 5. (3α,4α,5α)3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(48), and (3α,4β,5β)3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(49)

[0391] A solution of 1.1 g of 53, 0.36 g of potassium t-butoxide and 25ml of anhydrous THF was held at reflux for 2 h and worked up as in step4 of procedure A of example 18 to give 1.07 g of a crude product whichwas purified by HPLC to give 40 mg (4%) of 48 as crystals, mp 153-154°C. and 90 mg (8%) of 49 as solid, mp 136-140° C.

EXAMPLE 28

[0392] 5-Phenyl-2,3-dihydrospirobenzothiepine-3,1′-cyclohexane (57)

[0393] Step 1. 1-(Hydroxymethyl)-cyclohexanecarboxaldehyde (54)

[0394] To a cold (0° C.) mixture of 100 g (0.891 mole) ofcyclohexanecarboxaldehyde, 76.5 g of 37% of formaldehyde in 225 ml ofmethanol was added dropwise 90 ml of 1 N Sodium hydroxide in 1 h. Thereaction mixture was stirred at room temperature over 48 then wasevaporated to remove methanol. The reaction mixture was diluted withwater and extracted with methylene chloride. The organic layer waswashed with water, brine, and dried over sodium sulfate and concentratedunder vacuum to give 75 g (59.7%) of thick oil. Proton NMR and massspectra were consistent with the product.

[0395] Step 2. 1-(mesyloxymethyl)cyclohexanecarboxaldehyde (55)

[0396] To a cold (0° C.) mixture of alcohol 54 (75 g, 0.54 mole) and65.29 g (0.57 mole) of methanesulfonyl chloride in 80 ml of methylenechloride was added a solution of pyridine (47.96 g, 0.57 mole) in 40 mlof methylene chloride. The reaction mixture was stirred at roomtemperature for 18 h then quenched with water, acidified with conc. HCland extracted with methylene chloride. The organic layer was washed withwater, brine, and dried over sodium sulfate and concentrated undervacuum to give 91.63 g (77.8%) of thick oil. Proton NMR and mass spectrawere consistent with the product.

[0397] Step 3. 1-((2-Benzoylphenylthio)methyl)cyclohexanecarboxaldehyde(56)

[0398] A mixture of 69 g (0.303 mole) of 2-mercaptobenzophenone, 82 g(0.303 mole) of mesylate 55, 32 g of triethylamine, and 150 ml ofdiglyme was stirred and held at reflux for 24 h. The mixture was cooled,poured into dil. HCl and extracted with methylene chloride. The organiclayer was washed with 10% NaOH, water, brine, and dried over sodiumsulfate and concentrated under vacuum to remove excess diglyme. This waspurified by silica gel flush column (5% EtOAc:Hexane) and gave 18.6 g(75.9%) of yellow oil. Proton NMR and mass spectra were consistent withthe product.

[0399] Step 4. 5-Phenyl-2,3-dihydrospirobenzothiepine-3,1′-cyclohexane(57)

[0400] To a mixture of 6.19 g of zinc dust and 100 ml of dry DME wasadded TiCl,(16.8 g, 0.108 mole) . The reaction mixture was heated toreflux for 2 h. A solution of compound 56 (8.3 g, 0.023 mole) in 50 mlof DME was added dropwise to the reaction mixture in 1 h and the mixturewas held at reflux for 18 h. The mixture was cooled, poured into waterand extracted with ether. The organic layer was washed with water,brine, and dried over sodium sulfate, filtered through celite andconcentrated under vacuum. The residue was purified by HPLC (10% EtOAc:Hexane) to give 4.6 g (64%) of white solid, mp 90-91° C. Proton andcarbon NMR and mass spectra were consistent with the product.

EXAMPLE 29

[0401]8b-Phenyl-1a,2,3,8b-tetrahydrospiro(benzothiepino[4,5-b]oxirene-2,1′-cyclohexane)-4,4-dioxide(58)

[0402] To a solution of 57 (4.6 g, 15 mmole) in 50 ml chloroform undernitrogen was added 55% MCPBA (16.5 g, 52.6 mmole) portionwise withspatula. The reaction was held at reflux for 18 h and washed with 10%NaOH(3X), water, brine, and dried over sodium sulfate and concentratedunder vacuum to give 5 g of crude product. This was recrystallized fromHexane/EtOAc to give 4.31 g (81%) of yellow solid, mp 154-155° C. Protonand carbon NMR and mass spectra were consistent with the product.

EXAMPLE 30

[0403] trans-4-Hydroxy-5-phenyl-2,3,4,5-tetrahydrospiro(benzothiepine-3,1′-cyclohexane)-1,1-dioxide (59)

[0404] A mixture of 0.5 g (1.4 mmoles) of 58 , 20 ml of ethanol,10 ml ofmethylene chloride and 0.4 g of 10% Pd/C catalyst was hydrogenated with70 psi hydrogen for 3 h at room temperature. The crude reaction slurrywas filtered through Celite and evaporated to dryness. The residue waspurified by HPLC (10% EtOAc-Hexane, 25% EtOAc-Hexane). The firstfraction was 300 mg (60%) as a white solid, mp 99-100° C. Proton NMRshowed this was a trans isomer. The second fraction gave 200 mg of solidwhich was impure cis isomer.

EXAMPLE 31

[0405] cis-4-Hydroxy-5-phenyl-2,3,4,5-tetrahydrospiro(benzothiepine-3,1′-cyclohexane)-1,1-dioxide (60)

[0406] To a solution of 0.2 g (0.56 mmole) of 59 in 20 ml of CH₂Cl₂₁ wasadded 8 g of 50% NaOH and one drop of Aliquat-336(methyltricaprylylammonium chloride) phase transfer catalyst. Thereaction mixture was stirred for 10 h at room temperature. Twenty g ofice was added to the mixture and the mixture was extracted with CH₂Cl₂(3×10 ml) washed with water, brine and dried over MgSO₄ and concentratedin vacuo to recover 0.15 g of crude product. This was recrystallizedfrom Hexane/EtOAc to give 125 mg of white crystal, mp 209-210° C. .Proton and carbon NMR and mass spectra were consistent with the product.

EXAMPLE 32

[0407] (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine (61), and (3α,4β,5β)3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine (62)

[0408] To a solution of 0.5 g (1.47 mmole) of compound 47 in 5 ml ofanhydrous THF was added 0.17 g (1.47 mmole) of 95% potassium t-butoxide.The reaction mixture was stirred at room temperature for 18 h andquenched with 10 ml of 10% HCl. The organic was extracted into methylenechloride. The methylene chloride extract was dried over magnesiumsulfate and concentrated in vacuo. The residue was purified by HPLC (2%EtOAc-hexane) to give 47 mg of 61 in the second fraction and 38 mg of 62in the third fraction. Proton NMR and mass spectra were consistent withthe assigned structures.

EXAMPLE 33

[0409] (3α,4α,5α)3-Butyl-3ethyl-4-hydroxy-7-amino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,l-dioxide(63) and (3α,4α,5β)3-Butyl-3-ethyl-4-hydroxy-7-amino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(64)

[0410] An autoclave was charged with 200 mg of 37 in 40 cc ethanol and0.02 g 10% Pd/C. After purging with nitrogen the clave was charged with100 psi hydrogen and heated to 55 C. The reaction was monitored by TLCand mass spec and allowed to proceed until all of 37 was consumed. Afterthe reaction was complete the catalyst was filtered and the solvent wasremoved in vacuo and the only observable product was amine 63. This sameprocedure was used to produce 64 from 38.

EXAMPLE 34

[0411] (3α,4α,5α)3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3′-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(65), and (3α,4β,5β)3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3′-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(66).

[0412] Alkylation of e-methoxyphenol with 3-methoxybenzyl chlorideaccording to the procedure described in J. Chem. Soc, 2431 (1958) gave4-methoxy-2-(3′-methoxybenzyl)phenol in 35% yield. This material wasconverted to compound 65, mp 138.5-141.5° C., and compound 66, mp115.5-117.5° C., by the procedure similar to that in Example 18 methodB.

EXAMPLE 35

[0413] (3α,4α,5α)3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3′-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (67), and (3α,4β,5β)3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3′-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(68).

[0414] Alkylation of 4-methoxyphenol with 3-(trifluoromethyl)benzylchloride according to the procedure described in J. Chem. Soc. 2431(1958) gave 4-methoxy-2-(3′-(trifluoromethyl)benzyl)phenol. Thismaterial was converted to compound 67, mp 226.5-228° C., and compound68, mp 188-190° C., byu the procedure similar to that in Example 18method B.

EXAMPLE 36

[0415] (3α,4α,5α)3-Butyl-3-ethyl-5-(41-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(69), and (3a,4p,5S)3-Butyl-3-ethyl-5-(4′-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,`-dioxide(70).

[0416] Alkylation of 4-methoxyphenol with 4-fluorobenzyl chlorideaccording to the procedure described in J. Chem. Soc, 2431 (1958) gave4-methoxy-2-(4′-fluorobenzyl)phenol. This material was converted tocompound 69 and compound 70 by the procedure similar to that in Example18 method B.

EXAMPLE 37

[0417] (3α,4α,5α) 3-Butyl-3-ethyl-5- (31′-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (71),and (3α,4β,5β)3-Butyl-3-ethyl-5-(3′-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(72).

[0418] Alkylation of 4-methoxyphenol with 3-fluorobenzyl chlorideaccording to the procedure described in J. Chem. Soc, 2431 (1958) gave4-methoxy-2-(3′-fluorobenzyl)phenol. This material was converted tocompound 71 and compound 72 by the procedure similar to that in Example18 method B.

EXAMPLE 38

[0419] (3α,4α,5α)3-Butyl-3-ethyl-5-(2′-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(73), and (3α,4β,5β)3-Butyl-3-ethyl-5-(2′-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(74).

[0420] Alkylation of 4-methoxyphenol with 2-fluorobenzyl chlorideaccording to the procedure described in J. Chem. Soc, 2431 (1958) gave4-methoxy-2-(2′-fluorobenzyl)phenol. This material was converted tocompound 73 and compound 74 by the procedure similar to that in Example18 method B.

EXAMPLE 39

[0421] (3α,4α,5α)3-Butyl-7-bromo-3-ethyl-4-hydroxy-5-(3′-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(75), and (3α,4β,5β)3-Butyl-7-bromo-3-ethyl-4-hydroxy-5-(3′-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(76).

[0422] Alkylation of 4-bromophenol with 3-methoxybenzyl chlorideaccording to the procedure described in J. Chem. Soc, 2431 (1958) gave4-bromo-2-(3′-methoxybenzyl)phenol. This material was converted tocompound 75, mp 97-101.5° C., and compound 76, mp 102-106° C., by theprocedure similar to that in Example 18 method B.

EXAMPLE 40

[0423] (3α,4α,5α)3-Butyl-3-ethyl-7-fluoro-5-(4′-fluorophenyl)-4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(77), and (3α,4β,5β)3-Butyl-3-ethyl-7-fluoro-5-(4′-fluorophenyl)-4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(78).

[0424] Alkylation of 4-fluorophenol with 4-fluorobenzyl chlorideaccording to the procedure described in J. Chem. Soc, 2431 (1958) gave4-fluoro-2-(4′-fluorobenzyl)phenol. This material was converted tocompound 77, mp 228-230° C., and compound 78, mp 134.5-139° C., by theprocedure similar to that in Example 18 method B.

EXAMPLE 41

[0425] (3α,4α,5α)3-Butyl-3-ethyl-7-fluoro-4-hydroxy-5-(3′-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(79), and (3α,4β,5β)3-Butyl-3-ethyl-7-fluoro-40hydroxy-5-(3′-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(80).

[0426] Alkylation of ⁴-fluorophenol with 3-methoxybenzyl chlorideaccording to the procedure described in J. Chem. Soc, 2431 (1958) gave4-fluoro-2-(3′-methoxybenzyl)phenol. This material was converted tocompound 79, as a solid and compound 80, mp 153-155° C., by theprocedure similar to that in Example 18 method B.

EXAMPLE 42

[0427] (3α,4β,5β)3-Butyl-3-ethyl-5-(4′-fluorophenyl)-4-hydroxy-7-methylthio-2,3,4,⁵-tetrahydrobenzothiepine-1,1-dioxide(81).

[0428] A mixture of 0.68 (1.66 mmol) of compound 77, 0.2 g (5 mmol) ofsodium methanethiolate and 15 ml of anhydrous DMF was stirred at roomtemperature for 16 days. The reaction mixture was dilute with ether andwashed with water and brine and dried over M_(g)SO₄ The ether solutionwas concentrated in vacuo. The residue was purified by HPLC (20% ethylacetate in hexanes). The first fraction was impure (3α,4α,5α)3-butyl-3-ethyl-4-hydroxy-7-methylthio-5-(4′-fluorophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide.The second fraction was compound 81, mp 185-186.5° C.

EXAMPLE 43

[0429] (3α,4β,5β)3-Butyl-3-ethyl-5-(4′-fluorophenyl)-4-hydroxy-7-(1-pyrrolidinyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (82).

[0430] A mixture of 0.53 g (1.30 mmol) of compound 78 and 5 ml ofpyrrolidine was held at reflux for 1 h. The reaction mixture was dilutedwith ether and washed with water and brine and dried over MgSO₄. Theether solution was concentrated in vacuo. The residue was crystallizedfrom ether-hexanes to give compound 82, mp 174.5-177° C.

EXAMPLE 44

[0431] (3α,4β,5β)3-Butyl-3-ethyl-5-(4′-fluorophenyl)-4-hydroxy-7-(1-morpholinyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(83).

[0432] A mixture of 0.4 g (0.98 mnmol) of compound 78 and 5.0 g (56mnmol) of morpholine was held at reflux for 2 h and concentrated invacuo. The residue was diluted with ether (30 ml) and washed with waterand brine and dried over M9SO₄ The ether solution was concentrated invacuo. The residue was recrystallized from ether-hexanes to givecompound 83, mp 176.5-187.5° C.

EXAMPLE 45

[0433] (3α,4α,5α) 3-Butyl-3-ethyl-5- (4 ′-fluorophenyl)-4-hydroxy-7-methyl-2,3,4, 5-tetrahydrobenzothiepine-1,1-dioxiLde (84),and (3α,4β,5β)3-Butyl-3-ethyl-5-(4′-fluorophenyl)-4-hydroxy-7-methyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(85).

[0434] Alkylation of 4-methylphenol with 4-fluorobenzyl chlorideaccording to the procedure described in J. Chem. Soc, 2431 (1958) gave4-methyl-2-(4′-fluorobenzyl)phenol). This material was converted tocompound 84 and compound 85 by the procedure similar to that in Example18 method B.

EXAMPLE 46

[0435] (3α,4β,5β)3-Butyl-3-ethyl-4-hydroxy-5-(4′-hydroxyphenyl)-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(86), and (3α,4β,5β)3-Butyl-3-ethyl-4,7-dihydroxy-5-(4′-hydroxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(87).

[0436] To a solution of 0.52 (1.2 mmol) of compound 66 in 20 ml ofmethylene chloride was added 1.7 g (6.78 mmol) of born tribromide. Thereaction mixture was cooled to −78° C. and was stirred for 4 min. Anadditional 0.3 ml of boron tribromide was added to the reaction mixtureand the reaction mixture was stirred at −78° C. for 1 h and quenced with2 N HCl. The organic was extracted into ether. The ether layer waswashed with brine, dried over MgSO₄, and concentrated in vacuo. Theresidue (0.48 g) was purified by HPLC (30% ethyl acetate in hexanes).The first fraction was 0.11 g of compound 86 as a white solid, mp171.5-173° C. The second fraction was crystallized from chloroform togive 0.04 g of compound 87 as a white solid, mp 264° C. (dec).

EXAMPLE 47

[0437] (3α,4β,5β)3-Butyl-3-ethyl-4,7-dihydroxy-5-(4′-fluorophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(88).

[0438] Reaction of compound 70 with excess boron tribromide at roomtemperature and worked up as in Example 46 gave compound 88 after anHPLC purification.

EXAMPLE 48

[0439] (3α,4β,5β) 3-Butyl-3-ethyl-5- (4′-fluorophenyl) -4-hydroxy-7-(1-azetidinyl) -2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (89).

[0440] A mixture of 0.20 g (0.49 mmol) of compound 78, and 2.0 g (35mmol) of aztidine was held at reflux for 3 h and concentrated in vacuo.The residue was diluted with ether (30 ml) and washed with water andbrine and dried over MgSO4. The ether solution was concentrated on asteam bath. The separated crystals were filtered to give 0.136 g of 89as prisms, mp 196.5-199.5° C.

EXAMPLE 49

[0441] (3α,4α,5α)3-Butyl-3-ethyl-5-(3′-methoxyphenyl)-4-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(90). (3α,4β,5β)3-Butyl-3-ethyl-5-(3′-methoxyphenyl)-4-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(91).

[0442] A mixture of 0.4 g (0.95 mmol) of compound 79, 0.08 g (1.14 mmol)of sodium methanethiolate and 15 ml of anhydrous DMF was stirred at 60°C. for 2 h. An additional 1.4 mmol of sodium methanethiolate was addedto the reaction mixture and the mixture was stirred at 60° C. for anadditional 2 h. The reaction mixture was triturated with 100 ml of waterand extracted methylene chloride. The methylene chloride water mixturewas filtered through Celite and the methylene chloride layer was driedover MqSO₄ and concentrated in vacuo. The first fraction (0.1 g) wascompound 90, mp 117-121° C. The second fraction (0.16 g) was compound91, mp 68-76° C.

EXAMPLE 50

[0443] Preparation of polyethyleneglycol functionalized benzothiepine A.

[0444] A 50 ml rb flash under a nitrogen atmosphere was charged with0.54 g of M-Tres-5000 (Polyethyleneglycol Tresylate [methoxy-PEG-Tres,MW5000] purchased from Shearwater Polymers Inc., 2130 Memorial Parkway,SW, Huntsville, Ala. 35801), 0.055 g Compound No. 136, 0.326 C_(s)CO₃and 2 cc anhydrous acetonitrile. The reaction was stirred at 30 C for 5days and then the solution was filtered to remove salts. Next, theacetonitrile was removed under vacuum and the product was dissolved inTHF and then precipitated by addition of hexane. The polymer precipitatewas isolate by filtration from the solvent mixture (THF/hexane). Thisprecipitation procedure was continued until no Compound No. 136 wasdetected in the precipitated product (by TLC SiO2). Next, the polymerprecipitate was dissolved in water and filtered and the water solublepolymer was dialyzed for 48 hours through a cellulose dialysis tube(Spectrum® 7 ,45 mm×0.5 ft, cutoff 1,000 MW). The polymer solution wasthen removed from the dialysis tube and lyophilized until dried. The NMRwas consistent with the desired product A and gel permeationchromatography indicated the presence of a 4500 MW polymer and alsoverified that no free Compound No. 136 was present. This material wasactive in the IBAT in vitro cell assay.

EXAMPLE 51

[0445] Preparation of Compound 140

[0446] A 2-necked 50 ml round bottom Flask was charged with 0.42 g ofTres-3400 (Polyethyleneglycol Tresylate [Tres-PEG-Tres,MW 3400]purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW,Huntsville, Ala. 35801), 0.1 potassium carbonate, 0.100 g of CompoundNo. 111 and 5 ml anhydrous DMF. Stir for 6 days at 27° C. TLC indicatedthe disappearance of the starting Compound No. 111. The solution wastransferred to a separatory funnel and diluted with 50 cc methylenechloride and then extracted with water. The organic layer was evaporatedto dryness by means of a rotary evaporator. Dry wgt. 0.4875 g. Next, thepolymer was dissolved in water and then dialyzed for 48 hours at 40° C.through a cellulose dialysis tube (spectrum® 7 ,45 mm×0.5 ft, cutoff1,000 MW). The polymer solution was then removed from the dialysis tubeand lyophilized until dried 0.341 g). NMR was consistent with thedesired product B.

EXAMPLE 52

[0447]

[0448] A 10 cc vial was charged with 0.21 g of Compound No. 136 (0.5mmoles), 0.17 g (1.3 mmoles)potassium carbonate, 0.6 g (1.5 mmoles) of1,2-bis-(2-iodoethoxy)-ethane and 10 cc DMF. The reaction was stirredfor 4 days at room temperature and then worked up by washing withether/water. The ether layer was stripped to dryness and the desiredproduct Compound No. 134 was isolated on a silica gel column using 80/20hexane ethyl acetate.

EXAMPLE 53

[0449]

[0450] A two necked 25 ml round bottom Flask was charged with 0.5 g(1.24mmoles) of 69462, 13 mls of anhydrous DMF, 0.055 g of 60% NaHdispersion and 0.230 g (0.62 mmoles) of 1,2-Bis [2-iodoethoxylethane] at10° C. under nitogen. Next, the reaction was slowly heated to 40° C.After 14 hours all of the Compound No. 113 was consumed and the reactionwas cooled to room temperature and extracted with ether/water. The etherlayer was evaporated to dryness and then chromatographed on Silicage(80/20 ethyl acetate/hexane). Isolated Compound No. 112 (0.28 g) wascharacterized by NMR and mass spec.

EXAMPLE 55

[0451]

[0452] In a 50 ml round bottom Flask, add 0.7 g (1.8 mmoles) of CompoundNo. 136, 0.621 g of potassium carbonate, 6 ml DMF, and 0.33 g of 1,2-Bis[2-iodoethoxylethane]. Stir at 40 IC under nitrogen for 12 hours. Theworkup and isolation was the same procedure for Compound No. 112.

EXAMPLES 56 AND 57 (COMPOUND NOS. 131 AND 137)

[0453] The compositions of these compounds are shown in Table 3. Thesame procedure as for Example 55 except appropriate benzothiepine wasused.

EXAMPLE 58 (COMPOUND NO. 139)

[0454] The composition of this compound is shown in Table 3. Sameprocedure as for Example 55 with appropriate benzothiepine 1,6diiodohexane was used instead of 1,2-Bis [2-iodoethoxylethane].

EXAMPLE 59 (COMPOUND NO. 101)

[0455]

[0456] This compound is prepared by condensing the 7-NH₂ benzothiepinewith the 1,12-dodecane dicarboxylic acid or acid halide.

EXAMPLE 60 (Compound No. 104)

[0457]

[0458] 2-Chloro-4-nitrobenzophenone is reduced with triethylsilane andtrifluoromethane sulfonic acid to 2-chloro-4-nitrodiphenylmethane 32.Reaction of 32 with lithium sulfide followed by reacting the resultingsulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation ofXXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (seeScheme 5). Reduction of the sulfone-aldehyde XXV formaldehyde and 100psi hydrogen and 55 C for 12 hours catalyzed by palladium on carbon inthe same reaction vessel yields the substituted dimethylamine derivativeXXVIII. Cyclization of XXVII with potassium t-butoxide yields a mixtureof substituted amino derivatives of this invention Compound No. 104.

EXAMPLE 61

[0459]

[0460] A 1 oz. Fisher-porter bottle was charged with 0.14 g (0.34mmoles) of 70112, 0.97 gms (6.8 mmoles) of methyl iodide, and 7 ml ofanhydrous acetonitrile. Heat to 50° C. for 4 days. The quat. SaltCompound No. 192 was isolated by concentrating to 1 cc acetonitrile andthen precipitating with diethyl ether.

EXAMPLE 62

[0461]

[0462] A 0.1 g (0.159 mmoles) sample of Compound No. 134 was dissolvedin 15 ml of anhydrous acetonitrile in a Fischer-porter bottle and thentrimethylamine was bubbled through the solution for 5 minutes at 0° C.and then capped and warmed to room temperature. The reaction was stirredovernight and the desired product was isolated by removing solvent byrotary evaporation.

EXAMPLE 63 (COMPOUND NO. 295)

[0463]

[0464] Sodium Hydride 60% (11 mg, 0.27 mmnoles) in 1 cc of acetonitrileat 0° C. was reacted with 0.248 mmoles (0.10 g) of Compound No. 54 in2.5cc of acetonitrile at 0° C. Next, 0. (980 g 2.48 mmnoles) of 1,2-Bis[2-iodoethoxylethane]. After warming to room temperature, stir for 14hours. The product was isolated by column chromatography.

EXAMPLE 64 (COMPOUND NO. 286)

[0465]

[0466] Following a procedure similar to the one described in Example 86,infra (see Compound No. 118), the title compound was prepared andpurified as a colorless solid; mp 180-181° C.; ¹H NMR (CHCl₃) δ 0.85 (t,J=6 Hz, 3H, 0.92 (t, J=6 Hz, 3H), 1.24-1.42 (m, 2H), 1.46-1.56 (m, 1H),1.64-1.80 (m, 1H), 2.24-2.38 (m, 1H), 3.15 (AB, J_(AB)=15 Hz, Δv=42 Hz,2H), 4.20 (d, J=8 Hz, 1H), 5.13 (s, 2H), 5.53 (s, 1H), 6.46 (s, 1H),6.68 (s, 1H), 7.29-7.51 (m, 10H), 7.74 (d, J=8 Hz, 1H), 8.06 (d, J=8 Hz,1H). FABMS m/z 494 (M+H), HRMS calcd for (M+H) 494.2001, found 494.1993.Anal. Calcd. for C₂₈H₃₁NO₅S: C, 68.13; H, 6.33; N, 2.84. Found: C,68.19; H, 6.56; N, 2.74.

EXAMPLE 65 (COMPOUND NO. 287)

[0467]

[0468] Following a procedure similar to the one described in Example 89,infra (see Compound No. 121), the title compound was prepared andpurified as a colorless solid: mp 245-246° C., ¹H NMR (CDCl₃) δ 0.84 (t,J=6 Hz, 3H), 0.92 (t, J=6 Hz, 3H), 1.28, (d, J=8 Hz, 1H), 1.32-1.42 (m,1H), 1.48-1.60 (m, 1H), 1.64-1.80 (m, 1H), 2.20-2.36 (m, 1H), 3.09 (AB,JA =15 Hz, Δv=42 Hz, 2H), 3.97 (bs, 2H), 4.15 (d, J=8 Hz, 1H), 5.49 (s,1H), 5.95 (s, 1H), 6.54 (d, J=7 Hz, 1H), 7.29-7.53 (m, 5H), 7.88 (d, J=8Hz, 1H); ESMS 366 (M+Li). Anal. Calcd. for C₂₀H₂₅NO₃S: C, 66.82; H,7.01; N, 3.90. Found: C, 66.54; H, 7.20; N, 3.69.

EXAMPLE 66 (COMPOUND NO. 288)

[0469]

[0470] Following a procedure similar to the one described in Example 89,infra (see Compound No. 121), the title compound was prepared andpurified by silica gel chromatography to give the desired product as acolorless solid: mp 185-186° C.; ¹H NMR (CDCl₃) δ1.12 (s, 3H), 1.49 (s,3H), 3.00 (d, J=15 Hz, 1H), 3.28 (d, J=15 Hz, 1H), 4.00 (s, 1H), 5.30(s, 1H), 5.51 (s, 1H), 5.97 (s, 1H), 6.56 (dd, J=2.1, 8.4 Hz, 1H),7.31-7.52 (m, 5H), 7.89 (d, J=8.4 Hz, 1H). MS (FAB+) (M+H) m/z 332.

EXAMPLE 67 (COMPOUND NO. 289)

[0471]

[0472] Following a procedure similar to the one described in Example 89(see Compound No. 121), the title compound was prepared and purified bysilica gel chromatography to give the desired product as a white solid:mp 205-206° C.; ¹H NMR (CDCl₃) δ 0.80-0.95 (m, 6H), 1.10-1.70 (m, 7H),2.15 (m, 1H), 3.02 (d, J=15.3 Hz, 2H), 3.15 (d, J=15.1 Hz, 2H), 3.96 (s,br, 2H), 4.14 (d, J=7.8 Hz, 1H), 5.51 (s, 1H), 5.94 (d, J=2.2, 1H), 6.54(dd, J=8.5, 2.2 Hz, 1H), 7.28-7.50 (m, 6H), 7.87 (d, J=8.5 Hz, 1H). MS(FAB): m/z 388 (M+H).

EXAMPLE 68 (COMPOUND NO. 290)

[0473]

[0474] Following a procedure similar to the one described in Example 89,infra (see Compound No. 121), the title compound was prepared andpurified as a colorless solid: mp =96-98° C., ¹H NMR (CDCl₃) δ 0.92 (t,J=7 Hz, 6H), 1.03-1.70 (m, 11H), 2.21 (t, J=8 Hz, 1H), 3.09 (AB,J_(AB)=−18 Hz, Δv=38 Hz, 2H), 3.96 (bs, 2H), 4.14 (d, J=7 Hz, 1H), 5.51(s, 1H), 5.94 (s, 1H), 6.56 (d, J=9 Hz, 1H), 7.41-7.53 (m, 6H), 7.87 (d,J=8 Hz, 1H); FABMS m/z 416 (M+H).

EXAMPLE 69

[0475]

[0476] Following a procedure similar to the one described in Example 86,infra (see Compound No. 118), the title compound was prepared andpurified as a colorless solid: ¹H NMR (CDCl₃) δ 0.91 (t, J=7 Hz, 6H),1.02-1.52 (m, 11H), 1.60-1.70 (m, 1H), 2.23 (t, J=8 Hz, 1H), 3.12 (AB,JB =18 Hz, Δv=36 Hz, 2H), 4.18 (d, J=7 Hz, 1H), 5.13 (s, 2H), 5.53 (s,1H), 6.43 (s, 1H), 6.65 (s, 1H), 7.29-7.52 (m, 10H), 7.74 (d, J=9 Hz,1H), 8.03 (d, J=8 Hz, 1H); ESMS m/z 556 (M+Li).

EXAMPLE 70 (COMPOUND NO. 292)

[0477]

[0478] Following a procedure similar to the one descried in Example 89,infra (see Compound No. 121), the title compound was prepared andpurified as a colorless solid: mp =111-112.5° C., ¹H NMR (CDCl₃) δ 0.90(t, J=8 Hz, 6H), 1.03-1.50 (m, 10H), 1.55-1.70 (m, 2H), 2.18 (t, J=12Hz, 2H), 3.07 (AB, J_(AB)=15 Hz, Δv=45 Hz, 2H), 4.09 (bs, 2H), 5.49 (s,1H), 5.91 (s, 1H), 6.55 (d, J=9 Hz, 1H), 7.10 (t, J=7 Hz, 2H), 7.46 (t,J=6 Hz, 2H), 7.87 (d, J=9 Hz, 1H).

EXAMPLE 71 (COMPOUND NO. 293)

[0479]

[0480] During the preparation of Compound No. 290 from Compound No. 291using BBr₃, the title compound was isolated: ¹H NMR (CDCl₃) δ 0.85 (t,J=6 Hz, 6H), 0.98-1.60 (m, 10H), 1.50-1.66 (m, 2H), 2.16 (t, J=8 Hz,1H), 3.04 (AB, JA =15 Hz, Δv=41 Hz, 2H), 4.08 (s, 1H), 4.12 (s, 1H),5.44 (s, 1H), 5.84 (s, lH), 6.42 (d, J=9 Hz, 1H), 7.12 (d, J=8 Hz, 2H),7.16-7.26 (m, 10H), 7.83 (d, J=8 Hz, 1H); ESMS m/z 512 (M+Li).

EXAMPLE 72 (COMPOUND NO. 294)

[0481] Following a procedure similar to the one described in Example 60(Compound No. 104), the title compound was prepared and purified as acolorless solid: ¹H NMR (CDCl₃) δ 0.90 (t, J=6 Hz, 6H), 1.05-1.54 (m,9H), 1.60-1.70 (m, 1H), 2.24 (t, J=8 Hz, 1H), 2.80 (s, 6H), 3.05 (AB,J_(AB)=15 Hz, Δv=42 Hz, 2H), 4.05-4.18 (m, 2H), 5.53 (s, 1H), 5.93 (s,1H), 6.94 (d, J=9 Hz, 1H), 7.27-7.42 (m, 4H), 7.45 (d, J=8 Hz, 2H), 7.87(d, J=9 Hz, 1H); ESMS m/z 444 (M+H).

[0482] Structures of the compounds of Examples 33 to 72 are shown inTables 3 and 3A.

EXAMPLES 73-79, 87, 88 AND 91-102

[0483] Using in each instance a method generally described in those ofExamples 1 to 72 appropriate to the substituents to be introduced,compounds were prepared having the structures set forth in Table 3. Thestarting materials illustrated in the reaction schemes shown above werevaried in accordance with principles of organic synthesis well known tothe art to introduce the indicated substituents in the 4- and 5-positions (R³, R⁴, R⁵, R⁶) and in the indicated position on the benzoring (R^(x)).

[0484] Structures of the the compounds produced in Examples 73-102 areset forth in Tables 3 and 3A.

EXAMPLES 80-84

[0485] Preparation of 115, 116, 111, 113

[0486] Preparation of 4-chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene.

[0487] In a 500 ml 2-necked rb flask weigh out 68.3 gms phosphoruspentachloride (0.328 mole 1.1 eq). Add 50 mls chlorobenzene. Slowly add60 gms 2-chloro-5-nitrobenzoic acid (0.298 mole). Stir at room tempovernight under N2 then heat 1 hr at 50C.

[0488] Remove chlorobenzene by high vacuum. Wash residue with hexane.Dry wt-55.5 gms.

[0489] In the same rb flask, dissolve acid chloride (55.5 g 0.25 mole)from above with 100 mls anisole (about 3.4 eq). Chill solution with icebath while purging with N2. Slowly add 40.3 g aluminum chloride (1.2 eq0.3 mole). Stir under N₂ for 24 hrs.

[0490] After 24 hrs, the solution was poured into 300 mls iN HCl soln.(cold). Stir this for 15 min. Extract several times with diethyl ether.Extract organic layer once with 2% aqueous NaOH then twice with water.Dry organic layer with MgSO4, dry on vac line. Solid is washed well withether and then ethanol before drying. Wt=34.57 g (mixture of meta, orthoand para). Elemental theory found C 57.65 57.45 H 3.46 5.51 N 4.8 4.8 Cl12.15 12.16

[0491] With the next step of the reduction of the ketone withtrifluoromethane sulfonic aid and triethyl silane, crystallization withethyl acetate/hexane affords pure 4-chloro-3- [4-methoxy-phenylmethyl]-nitrobenzene. 4-Chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene was thenreacted as specified in the synthesis of 117 and 118 from2-chloro-4-nitrophenylmethane. From these procedures 115 and 116 can besynthesized. Compounds 111 and 113 can be synthesized from the procedureused to prepare compound 121.

[0492] Compound 114 can be prepared by reaction of 116 with ethylmercaptan and aluminum trichloride.

EXAMPLES 85 AND 86

[0493] Preparation of 117 and 118

[0494] 2-Chloro-4-nitrobenzophenone is reduced with triethylsilane andtrifluoromethane sulfonic acid to 2-chloro-4-nitrodiphenylmethane 32.Reaction of 32 with lithium sulfide followed by reacting the resultingsulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation ofXXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIII.Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehydeXXIV (see Scheme 5).

[0495] The sulfone-aldehyde (31.8 g) was dissolved in ethanol/tolueneand placed in a parr reactor with 100 ml toluene and 100 ml of ethanoland 3.2 g of 10% Pd/C and heated to 55 C and 100 psi of hydrogen gas for14 hours. The reaction was then filtered to remove the catalyst. Theamine product (0.076 moles, 29.5 g) from this reaction was then reactedwith benzyl chloroformate (27.4 g) in toluene in the presence of 35 g ofpotassium carbonate and stirred at room temperature overnight. Afterwork up by extraction with water, the CBZ protected amine product wasfurther purified by precipitation from toluene/hexane.

[0496] The CBZ protected amine product was then reacted with 3equivalents of potassium t-butoxide in THF at 0 C to yield compounds 117and 118 which were separated by silica gel column chromatography.

EXAMPLES 89 AND 90

[0497] Preparation of 121 or 122

[0498] Compound 118 (.013 moles, 6.79 g) is dissolved in 135 ml of drychloroform and cooled to -78 C, next 1.85 ml of boron tribromide (4.9 g)was added and the reaction is allowed to warm to room temperature.Reaction is complete after 1.5 hours. The reaction is quenched byaddition of 10% potassium carbonate at 0 C and extract with ether.Removal of ether yields compound 121. A similar procedure can be used toproduce 122 from 117.

EXAMPLES 93-96

[0499] Compounds 126, 127, 128 and 129 as set forth in Table 3 wereprepared substantially in the manner described above for compounds 115,116, 111 and 113, respectively, except that fluorobenzene was used as astarting material in place of anisole. TABLE 3 Specific Compounds(#102-111, 113-130, 132-134, 136, 138, 142-144, 262-296)

Cp# R¹ R² R³ R⁴ R⁵ R⁶ (R^(x))q 102 Et- n-Bu- HO— H— Ph— H— I⁻, 7-(CH₃)₃N^(+—) 103 n-Bu- Et- HO— H— Ph— H— I⁻, 7- (CH₃)₃N^(+—) 104 Et-n-Bu- HO— H— Ph— H— 7-(CH₃)₂N — 105 Et- n-Bu- HO— H— Ph— H— 7- CH₃SO₂NH—106 Et- n-Bu- HO— H— Ph— H— 7-Br—CH₂— CONH— 107 n-Bu- Et- HO— H— p-n- H—7-NH₂— C₁₀H₂₁—O— Ph— 108 Et- n-Bu- HO— H— Ph— H— 7- C₅H₁₁CONH— 109 Et-n-Bu- HO— H— p-n- H— 7-NH₂— C₁₀H₂₁—O— Ph— 110 Et- n-Bu- HO— H— Ph— H—7-CH₃CONH— 111 n-Bu- Et- HO— H— p-HO—Ph— H— 7-NH₂— 113 Et- n-Bu- HO— H—p-HO—Ph— H— 7-NH₂— 114 Et- n-Bu- HO— H— p-CH₃O—Ph— H— 7-NH₂— 115 n-Bu-Et- HO— H— p-CH₃O—Ph— H— 7-NH—CBZ 116 Et- n-Bu- HO— H— p-CH₃O—Ph— H—7-NH—CBZ 117 n-Bu- Et- HO— H— Ph— H— 7-NH—CBZ 118 Et- n-Bu- HO— H— Ph—H— 7-NH—CBZ 119 Et- n-Bu- HO— H— Ph— H— 7-NHCO₂-t- Bu 120 n-Bu- Et- HO—H— Ph— H— 7-NHCO₂-t- Bu 121 Et- n-Bu- HO— H— Ph— H— 7-NH₂— 122 n-Bu- Et-HO— H— Ph— H— 7-NH₂— 123 Et- n-Bu- HO— H— Ph— H— 7-n-C₆H₁₃— NH— 124n-Bu- Et- HO— H— Ph— H— 7-n-C₆H₁₃— NH— 125 Et- n-Bu- HO— H— Ph— H— I⁻,8- (CH₃)₃)N⁺ (CH₂CH₂O)₃— 126 n-Bu- Et- HO— H— p-F—Ph— H— 7-NH—CBZ 127n-Bu- Et- HO— H— p-F—Ph— H— 7-NH₂— 128 Et- n-Bu- HO— H— p-F—Ph— H—7-NH—CBZ 129 Et- n-Bu- HO— H— p-F—Ph— H— 7-NH₂— 130 Et- n-Bu- HO— H— Ph—H— I⁻, 8- (CH₃)₃N⁺ C₆H₁₂O— 132 Et- n-Bu- HO— H— Ph— H— 8-phthal- imidyl-C₆H₁₂O— 133 Et- n-Bu- HO— H— Ph— H— 8-n- C₁₀H₂₁— 134 Et- n-Bu- HO— H—Ph— H— 8- I- (C₂H₄O)₃— 136 Et- n-Bu- HO— H— Ph— H— 8- HO— 138 n-Bu- Et-HO— H— Ph— H— 8- CH₃CO₂— 142 Et- n-Bu- H— HO— H— m-CH₃O—Ph— 7-CH₃S— 143Et- n-Bu- HO— H— m-CH₃O—Ph— H— 7-CH₃S— 144 Et- n-Bu- HO— H— p-F—Ph— H—7-(N)- azetidine 262 Et- n-Bu- HO— H— m-CH₃O—Ph— H— 7-CH₃O— 263 Et-n-Bu- H— HO— H— m-CH₃O—Ph— 7-CH₃O— 264 Et- n-Bu- HO— H— m-CF₃—Ph— H—7-CH₃O— 265 Et- n-Bu- H— HO— H— m-CF₃—Ph— 7-CH₃O— 266 Et- n-Bu- HO— H—m-HO—Ph— H— 7-HO— 267 Et- n-Bu- HO— H— m-HO—Ph— H— 7-CH₃O— 268 Et- n-Bu-HO— H— p-F—Ph— H— 7-CH₃O— 269 Et- n-Bu- H— HO— H— p-F—Ph— 7-CH₃O— 270Et- n-Bu- HO— H— p-F—Ph— H— 7-HO— 271 Et- n-Bu- HO— H— m-CH₃O—Ph— H—7-Br— 272 Et- n-Bu- H— HO— H— m-CH₃O—Ph— 7-Br— 273 Et- n-Bu- H— HO— H—p-F—Ph— 7-F— 274 Et- n-Bu- HO— H— p-F—Ph— H— 7-F— 275 Et- n-Bu- H— HO—H— m-CH₃O—Ph— 7-F— 276 Et- n-Bu- HO— H— m-CH₃O—Ph— H— 7-F— 277 Et- n-Bu-HO— H— m-F—Ph— H— 7-CH₃O— 278 Et- n-Bu- H— HO— H— o-F—Ph— 7-CH₃O— 279Et- n-Bu- H— HO— H— m-F—Ph— 7-CH₃O— 280 Et- n-Bu- HO— H— o-F—Ph— H—7-CH₃O— 281 Et- n-Bu- HO— H— p-F—Ph— H— 7-CH₃S— 282 Et- n-Bu- HO— H—p-F—Ph— H— 7-CH₃— 283 Et- n-Bu- H— HO— H— p-F—Ph— 7-CH₃— 284 Et- n-Bu-HO— H— p-F—Ph— H 7-(N)- morpholine 285 Et- n-Bu- HO— H— p-F—Ph— H 7-(N)-pyrroli dine 286 Et- Et- HO— H— Ph— H— 7-NH—CBZ- 287 Et- Et- HO— H— Ph—H— 7-NH₂— 288 CH₃— CH₃— HO— H— Ph— H— 7-NH₂— 289 n- n- HO— H— Ph— H—7-NH₂— C₃H₇— C₃H₇— 290 n-Bu- n-Bu- HO— H— Ph— H— 7-NH₂— 291 n-Bu- n-Bu-HO— H— Ph— H— 7-NH—CBZ- 292 n-Bu- n-Bu- HO— H— p-F—Ph— H— 7-NH₂— 293n-Bu- n-Bu- HO— H— Ph— H— 7-PhCH₂N— 294 n-Bu- n-Bu- HO— H— Ph— H—7-(CH₃)₂N— 295 Et- n-Bu- HO— H— p-I- H— 7-NH₂— (C₂H₄O)₃— Ph— 296 Et-n-Bu- HO— H— I^(−, p-) H— 7-NH₂— (CH₃)₃N⁺ (C₂H₄O)₃—Ph—

[0500]

EXAMPLES 104-231

[0501] Using in each instance a method generally described in those ofExamples 1 to 72 appropriate to the substituents to be introduced,including where necessary other common synthesis expedients well knownto the art, compounds are prepared having the structures set forth inTable 4. The starting materials illustrated in the reaction schemesshown above are varied in accordance with principles of organicsynthesis well known to the art in order to introduce the indicatedsubstituents in the 4- and 5-positions (R³, R⁴, R⁵, R⁶) and in theindicated position on the benzo ring (R^(x)). TABLE 4 Alternativecompounds #1 (#302-312, 314-430)

Cpd# R⁵ (R^(x))q 302 p-F—Ph— 7-(1-aziridine) 303 p-F—Ph— 7-EtS— 304p-F—Ph— 7-CH₃S(O)— 305 p-F—Ph— 7-CH₃S(O)₂— 306 p-F—Ph— 7-PhS— 307p-F—Ph— 7-CH₃S— 9-CH₃S— 308 p-F—Ph— 7-CH₃O— 9-CH₃O— 309 p-F—Ph— 7-Et-310 p-F—Ph— 7-iPr- 311 p-F—Ph— 7-t-Bu- 312 p-F—Ph— 7-(1-pyrazole)- 314m-CH₃O—Ph 7-(1-azetidine) 315 m-CH₃O—Ph— 7-(1-aziridine) 316 m-CH₃O—Ph—7-EtS— 317 m-CH₃O—Ph— 7-CH₃S(O)— 318 m-CH₃O—Ph— 7-CH₃S(O)₂— 319m-CH₃O—Ph— 7-PhS— 320 m-CH₃O—Ph 7-CH₃S— 9-CH₃S— 321 m-CH₃O—Ph 7-CH₃O—9-CH₃O— 322 m-CH₃O—Ph 7-Et- 323 m-CH₃O—Ph 7-iPr- 324 m-CH₃O—Ph 7-t-Bu-6-CH₃O— 325 p-F—Ph— 7-CH₃O— 8-CH₃O— 326 p-F—Ph— 7-(1-azetidine) 9-CH₃—7-EtS— 327 p-F—Ph— 9-CH₃— 328 p-F—Ph— 7-CH₃S(O)— 9-CH₃— 329 p-F—Ph—7-CH₃S(O)₂— 9-CH_(3—) 330 p-F—Ph— 7-PhS— 9-CH₃— 7-CH₃S— 331 p-F—Ph—9-CH₃— 332 p-F—Ph— 7-CH₃O— 9-CH₃— 333 p-F—Ph— 7-CH₃— 9-CH₃— 334 p-F—Ph—7-CH₃O— 9-CH₃O— 335 p-F—Ph— 7-(1-pyrrole) 336 p-F—Ph—7-(N)N′-methylpiperazine 337 p-F—Ph— Ph— 338 p-F—Ph— 7-CH₃C(═CH₂)— 339p-F—Ph— 7-cyclpropyl 340 p-F—Ph— 7-(CH₃)₂NHN— 341 p-F—Ph—7-(N)-azetidine 9-CH₃S— 342 p-F—Ph— 7-(N-pyrrolidine) 9-CH₃S— 343p-F—Ph— 7-(CH₃)₂N— 9-CH₃S— 344 m-CH₃O—Ph— 7-(1-pyrazole) 345 m-CH₃O—Ph—7-(N)N′-methylpiperazine 346 m-CH₃O—Ph— Ph— 347 m-CH₃O—Ph— 7-CH₃C(═CH₂)—348 m-CH₃O—Ph— 7-cyclopropyl 349 m-CH₃O—Ph— 7-(CH₃)₂NHN— 350 m-CH₃O—Ph—7-(N)-azetidine 9-CH₃S— 351 m-CH₃O—Ph— 7-(N-pyrrolidine)- 9-CH₃S— 352m-CH₃O—Ph— 7-(CH₃)₂N— 9-CH₃S— 353 m-CH₃O—Ph— 6-CH₃O— 7-CH₃O— 8-CH₃O— 354m-CH₃O—Ph 7-(1-azetidine) 9-CH₃— 355 m-CH₃O—Ph— 7-EtS— 9-CH₃— 356m-CH₃O—Ph— 7-CH₃S(O)— 9-CH₃— 357 m-CH₃O—Ph— 7-CH₃S(O)₂— 9-CH₃— 358m-CH₃O—Ph— 7-PhS— 9-CH₃— 359 m-CH₃O—Ph— 7-CH₃S— 9-CH₃— 360 m-CH₃O—Ph—7-CH₃O— 9-CH₃— 361 m-CH₃O—Ph— 7-CH₃— 9-CH₃— 362 m-CH₃O—Ph— 7-CH₃O—9-CH₃O— 363 thien-2-yl 7-(1-aziridine) 364 thien-2-yl 7-EtS— 365thien-2-yl 7-CH₃S(O)— 366 thien-2-yl 7-CH₃S(O)₂— 367 thien-2-yl 7-PhS—368 thien-2-yl 7-CH₃S— 9-CH₃S— 369 thien-2-yl 7-CH₃O— 9-CH₃O— 370thien-2-yl 7-Et- 371 thien-2-yl 7-iPr- 372 thien-2-yl 7-t-Bu- 373thien-2-yl 7-(1-pyrrole)- 374 thien-2-yl 7-CH₃O— 375 thien-2-yl 7-CH₃S—376 thien-2-yl 7-(1-azetidine) 377 thien-2-yl 7-Me- 378 5-Cl-thien-2-yl7-(1-azetidine) 379 5-Cl-thien-2-yl 7-(1-aziridine) 380 5-Cl-thien-2-yl7-EtS— 381 5-Cl-thien-2-yl 7-CH₃S(O)— 382 5-Cl-thien-2-yl 7-CH₃S(O)₂—383 5-Cl-thien-2-yl 7-PhS— 384 5-Cl-thien-2-yl 7-CH₃S— 9-CH₃S— 3855-Cl-thien-2-yl 7-CH₃O— 9-CH₃O— 386 5-Cl-thien-2-yl 7-Et- 3875-Cl-thien-2-yl 7-iPr- 388 5-Cl-thien-2-yl 7-t-Bu- 389 5-Cl-thien-2-yl7-CH₃O— 390 5-Cl-thien-2-yl 7-CH₃S— 391 5-Cl-thien-2-yl 7-Me 392thien-2-yl 7-(1-azetidine) 9-CH₃— 393 thien-2-yl 7-EtS— 9-CH₃— 394thien-2-yl 7-CH₃S(O)— 9-CH₃— 395 thien-2-yl 7-CH₃S(O)₂— 9-CH₃— 396thien-2-yl 7-PhS— 9-CH₃— 397 thien-2-yl 7-CH₃S— 9-CH₃— 398 thien-2-yl7-CH₃O— 9-CH₃— 399 thien-2-yl 7-CH₃— 9-CH₃— 400 thien-2-yl 7-CH₃O—9-CH₃O— 401 thien-2-yl 7-(1-pyrazrole) 402 thien-2-yl7-(N)N′-methylpiperazine 403 thien-2-yl Ph— 404 thien-2-yl 7-CH₃C(═CH₂)—405 thien-2-yl 7-cyclpropyl 406 thien-2-yl 7-(CH₃)₂NHN 407 thien-2-yl7-(N)-azetidine 9-CH₃S— 408 thien-2-yl 7-(N-pyrrolidine) 9-CH₃S— 409thien-2-yl 7-(CH₃)₂N— 9-CH₃S— 411 5-Cl-thien-2-yl 7-(1-pyrazrole) 4125-Cl-thien-2-yl 7-(N)N′-methylpiperazine 413 5-Cl-thien-2-yl Ph— 4145-Cl-thien-2-yl 7-CH₃C(═CH₂)— 415 5-Cl-thien-2-yl 7-cyclopropyl 4165-Cl-thien-2-yl 7-(CH₃)₂NHN— 417 5-Cl-thien-2-yl 7-(N)-azetidine 9-CH₃S—418 5-Cl-thien-2-yl 7-(N-pyrrolidine)- 9-CH₃S— 419 5-Cl-thien-2-yl7-(CH₃)₂N— 9-CH₃S— 420 5-Cl-thien-2-yl 7-(1-azetidine) 9-CH₃— 4215-Cl-thien-2-yl 7-EtS— 9-CH₃— 422 5-Cl-thien-2-yl 7-CH₃S(O)— 9-CH₃— 4235-Cl-thien-2-yl 7-CH₃S(O)₂— 9-CH₃— 424 5-Cl-thien-2-yl 7-PhS— 9-CH₃— 4255-Cl-thien-2-yl 7-CH₃S— 9-CH₃— 426 5-Cl-thien-2-yl 7-CH₃O— 9-CH₃— 4275-Cl-thien-2-yl 7-CH₃— 9-CH₃— 428 5-Cl-thien-2-yl 7-CH₃O— 9-CH₃O— 429thien-2-yl 6-CH₃O— 7-CH₃O— 8-CH₃O— 430 5-Cl-thien-2-yl 6-CH₃O— 7-CH₃O—8-CH₃O—

EXAMPLES 232-1394

[0502] Using in each instance a method generally described in those ofExamples 1 to 72 appropriate to the substituents to be introduced,including where necessary other common synthesis expedients well knownto the art, compounds are prepared having the structures set forth inTable 1. The starting materials illustrated in the reaction schemesshown above are varied in accordance with principles of organicsynthesis well known to the art in order to introduce the indicatedsubstituents in the 4- and 5-positions (R3, R⁴, R⁵, R⁶) and in theindicated position on the benzo ring (R_(x)).

EXAMPLE 1395

[0503] Dibutyl 4-fluorobenzene dialdehyde

[0504] Step 1: Preparation of dibutyl 4-fluoro benzene dialdehyde

[0505] To a stirred solution of 17.5 g (123 mmol) of2,5-difluorobenzaldehyde (Aldrich) in 615 mL of DMSO at ambienttemperature was added 6.2 g (135 mmol) of lithium sulfide (Aldrich). Thedark red solution was stirred at 75 C for 1.5 hours, or until thestarting material was completely consumed, and then 34 g (135 mmol) ofdibutyl mesylate aldehyde was added at about 50 C. The reaction mixturewas stirred at 75 C for three hours or until the reaction was completed.The cooled solution was poured into water and extracted with ethylacetate. The combined extracts were washed with water several times,dried (MgSO₄) and concentrated in vacuo. Silica gel chromatographicpurification of the crude product gave 23.6 g (59%) of fluorobenzenedialdehyde as a yellow oil: ¹H NMR (CDCl3) d 0.87 (t, J=7.05 Hz, 6H),1.0-1.4 (m, 8H), 1.5-1.78 (m, 4H), 3.09 (s, 2H), 7.2-7.35 (m, 1H),7.5-7.6 (m, 2H), 9.43 (s, 1H), 10.50 (d, J=2.62 Hz, 1H).

[0506] Step 2: Preparation of dibutyl 4-fluorobenzyl alcohol

[0507] To a solution of 22.6 g (69.8 mmol) of the dialdehyde obtainedfrom Step 1 in 650 mL of THF at −60 C was added 69.8 mL (69.8 mmol) ofDIBAL (1M in THF) via a syringe. The reaction mixture was stirred at −40C for 20 hours. To the cooled solution at −40 C was added sufficientamount of ethyl acetae to quench the excess of DIBAL, followed by 3 NHCl. The mixture was extracted with ethyl acetate, washed with water,dried (MgSO₄), and concentrated in vacuo. Silica gel chromatographicpurification of the crude product gave 13.5 g (58%) of recoveredstarting material, and 8.1 g (36%) of the desired fluorobenzyl alcoholas a colorless oil: ¹H NMR (CDCl₃) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4(m, 8H), 1.5-1.72 (m, 4H), 1.94 (br s, 1H), 3.03 (s, 2H), 4.79 (s, 2H),6.96 (dt, J=8.46, 3.02 Hz, 1H), 7.20 (dd, J=9.47, 2.82 Hz, 1H), 7.42(dd, J=8.67, 5.64, IH), 9.40 (s, 1H).

[0508] Step 3: Preparation of dibutyl 4-fluorobenzyl bromide

[0509] To a solution of 8.1 g (25 mmol) of benzyl alcohol obtained fromStep 2 in 100 mL of DMF at −40 C was added 47 g (50 mmol) ofbromotriphenyphosphonium bromide (Aldrich). The resulting solution wasstirred cold for 30 min, then was allowed to warm to 0 C. To the mixturewas added 10% solution of sodium sulfite and ethyl acetate. The extractwas washed a few times with water, dried (MgSO4), and concentrated invacuo. The mixture was stirred in small amount of ethyl acetate/hexanemixture (1:4 ratio) and filtered through a pad of silica gel, elutingwith same solvent mixture. The combined filtrate was concentrated invacuo to give 9.5 g (98%) of the desired product as a colorless oil: ¹HNMR (CDCl₃) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.55-1.78 (m,4H), 3.11 (s, 2H), 4.67 (s, 2H), 7.02 (dt, J=8.46, 3.02 Hz, 1H), 7.15(dd, J=9.47, 2.82 Hz, 1H), 7.46 (dd, J=8.67, 5.64, lH), 9.45 (s, 1H).

[0510] Step 4: Preparation of sulfonyl 4-fluorobenzyl bromide

[0511] To a solution of 8.5 g (25 mmol) of sulfide obtained from Step 3in 200 mL of CH₂Cl₂ at 0° C. was added 15.9 g (60 mmol) of mCPBA (64%peracid). The resulting solution was stirred cold for 10 min, then wasallowed to stirred ambient temperature for 5 hours. To the mixture wasadded 10% solution of sodium sulfite and ethyl acetate. The extract waswashed several times with saturated Na₂CO₃, dried (MgSO₄), andconcentrated in vacuo to give 10.2 g (98%) of the desired product as acolorless oil: ¹H NMR (CDCl₃) d 0.91 (t, J=7.05 Hz, 6H), 1.03-1.4 (m,8H), 1.65-1.82 (m, 2H), 1.90-2.05 (m, 2H), 3.54 (s, 2H), 5.01 (s, 2H),7.04-7.23 (m, 1H), 7.30 (dd, J=8.87, 2.42 Hz, 1H), 8.03 (dd, J=8.86,5.64, 1H), 9.49 (s, 1H).

EXAMPLE 1396

[0512]

[0513] Generic Scheme X: The nucleophilic substitution of anappropriately substituted 2-fluorobenzaldehyde with lithium sulfide orother nucleophilic sulfide anion in polar solvent (such as DMF, DMA,DMSO . . . etc), followed by the addition of dialkyl mesylate aldehyde(X), provided a dialkyl benzene dialdehyde Y. DIBAL reduction of thedialdehyde at low temperature yielded benzyl alcohol monoaldehyde Z.Conversion of benzyl alcohol to benzyl bromide, followed by oxidation ofsulfide to sulfone yielded the key intermediate W.

[0514] Preparation of N-propylsulfonic acid

[0515] To a solution of 51 mg (111 μm) Compound X in ethanol (400 μl)was added 1,3 propane sultone (19.5 μl, 222 um). The reaction wasstirred in a sealed vial at 55° C. for 25 hr. Sample was concentratedunder a nitrogen stream and purified by reversed phase chromatographyusing acetonitrile/water as eluent (30-45%) and afforded the desiredmaterial as an off-white solid (28.4 mg, 44%): ¹H NMR (CDCL₃) d0.82-0.96 (m, 6H), 1.11-1.52 (m of m, 10H), 1.58-1.72 (m, 1H), 2.08-2.21(m, 1H), 2.36-2.50 (m, 2H), 2.93 (s, 6H), 3.02-3.22 (m of m, 5H),3.58-3.76 (m, 2H), 4.15 (s, 1H), 5.51 (s, 1H), 6.45-6.58 (m, 1H),6.92-7.02 (m, 1H), 7.35-7.41 (m, 1H), 7.41-7.51 (m, 2H), 8.08 (d, J=8.1Hz, 1H), 8.12-8.25 (m, 1H); MS ES- M-H m/z 579.

EXAMPLE 1397

[0516] The 7-fluoro, 9-fluoro and 7,9-difluoro analogs of benzothiepinecompounds of this invention can be reacted with sulfur and nitrogennucleophiles to give the corresponding sulfur and nitrogen substitutedanalogs. The following example demonstrates the synthesis of theseanalogs.

[0517]3,3-Dibutyl-5a-(4′-fluorophenyl)-4a-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide.

[0518] A mixture of 0.4 g Of3,3-dibutyl-7-fluoro-5a-(4′-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide,prepared by previously described method, 0.12 g of sodiummethanethiolate and 20 ml of DMF was stirred at 50 C for 3 days. Anadditional 0.1 g of sodium methanethiolate was added to the reactionmixture and the mixture was stirred for additional 20 h at 50 C then wasconcentrated in vacuo. The residue was triturated with water andextracte wiith ether. The ether extract was dried over MgSO₄ andconcentrated in vacuo to 0.44 g of an oil. Purification by HPLC (10%EtOAc in hexane) gave 0.26 g of needles, mp 164-165.5 % C.

[0519]3,3-Dibutyl-9-dimethylamino-7-fluoro-5a-(4′-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxideand7,9-Bis(dimethylamino)-3,3-dibutyl-5a-(4′-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide.

[0520] A solution of 0.105 g of3,3-dibutyl-7,9-difluoro-5a-(4′-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, prepared by the methoddescribed previously, in 20 ml of 2 N dimethylamine in THF was heated at160 C in a sealed Parr reactor overnight. The reaction mixture wascooled and concentrated in vacuo. The residue was triturated with 25 mlof water and extracted with ether. The ether extract was dried overMgSO₄ and concentrated in vacuo. The resdue was purified by HPLC (10%EtOAc in hexane) to give 35 mg of an earlier fraction which wasidentified as3,3-dibutyl-9-dimethylamino-7-fluoro-5a-(4′-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide,MS (CI) m/e 480 (M⁺+1), and 29 mg of a later fraction which wasidentified as7,9-bis(dimethylamino)-3,3-dibutyl-5a-(4′-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide,MS (CI) m/e 505 (M⁺+1).

[0521] The compounds of this invention can also be synthesized usingcyclic sulfate (XL, below) as the reagent as shown in the followingschemes XI and XII. The following examples describe a procedure forusing the cyclic sulfate as the reagent.

[0522] Scheme XI illustrates yet another route tobenzothiepine-1,1-dioxides, particularly 3,3-dialkyl analogs, startingfrom the thiophenol XVIIIA. Thiophenol XVIIIA can be reacted with cyclicsulfate XL to give the alcohol XLI which can be oxidized to yield thealdehyde XLII. Aldehyde XLII itself can be further oxidized to give thesulfone XLIII which can be cyclized to give a stereoisomeric mixture ofbenzothiepine XLIVa and XLIVb.

[0523] Thiophenol XVIIIA can be prepared according to Scheme 3 aspreviously discussed and has the following formula:

[0524] wherein R⁵, R^(x) and q are as previously defined for thecompounds of formula I. Cyclic sulfate XL can be prepared according tosynthetic procedures known in the art and has the following formula:

[0525] wherein R¹ and R² are as previously defined for the compounds offormula I. Preferably, R¹ and R² are alkyl; more preferably, they areselected from the group consisting of methyl, ethyl, propyl, isopropyl,n-butyl, iso-butyl, sec-butyl, tert-butyl, and pentyl; and still morepreferably, R¹ and R² are n-butyl.

[0526] In the process of Scheme XI, thiophenol XVIIIA is initiallyreacted with cyclic sulfate XL. This reaction preferably is conducted inan aprotic solvent such as methoxyethyl ether. While the reactionconditions such as temperature and time are not narrowly critical, thereaction preferably is allowed to proceed at about room temperature forabout two hours. The reaction preferably employs an approximatelystoichiometric ratio of the starting materials, with a slight excess ofcyclic sulfate XL being preferred. Reaction time and yield can beimproved by using about 1.01 to 1.3 equivalents of cyclic sulfate XL foreach equivalent of thiophenol XVIIIA present. More preferably, thisratio is about 1.1 equivalents of cyclic sulfate XL for each equivalentof thiophenol XVIIIA present.

[0527] In the process of the invention, thiophenol XVIIIA also istreated with an abstracting agent. The abstracting agent can be added tothe solvent containing thiophenol XVIIIA prior to, concurrently with, orafter the addition of cyclic sulfate XL. Without being held to aparticular theory, it is believed the abstracting agent removes thehydrogen atom from the mercaptan group attached to the benzene ring ofthiophenol XVIIIA. The resulting sulfur anion of the thiophenol thenreacts with cyclic sulfate XL to open the sulfate ring. The sulfur anionof the thiophenol then bonds with a terminal carbon atom of the openring sulfate. The terminal group at the unbonded end of the open ringsulfate is the sulfate group.

[0528] The abstracting agent generally is a base having a pH greaterthan about 10. Preferably, the base is an alkali metal hydride such assodium hydride, lithium hydride or potassium hydride; more preferably,the base is sodium hydride. A slight excess of abstracting agent ispreferred relative to thiophenol XVIIIA. Reaction time and yield isimproved by using about 1.0 to about 1.1 equivalents of abstractingagent for each equivalent of thiophenol XVIIIA present. More preferably,this ratio is about 1.1 equivalents of abstracting agent for eachequivalent of thiophenol XVIIIA present.

[0529] The sulfate group of the intermediate product of the reaction ofthiophenol XVIIIA with cyclic sulfate XL is then removed, preferably byhydrolysis, to yield alcohol XLI. Suitable hydrolyzing agents includemineral acids, particularly hydrochloric acid and sulfuric acid.

[0530] The several reactions involving thiophenol XVIIIA, cyclic sulfateXL, the abstracting agent and the hydrolyzing agent can take place insitu without the need for isolation of any of the intermediatesproduced.

[0531] Alcohol XLI is then isolated by conventional methods (forexample, extraction with aqueous methyl salicylate) and oxidized usingstandard oxidizing * agents to aldehyde XLII. Preferably, the oxidizingagent is sulfur trioxide or pyridinium chlorochromate, and morepreferably, it is pyridinium chlorochromate. The reaction is conductedin a suitable organic solvent such as methylene chloride or chloroform.

[0532] Aldehyde XLII is then isolated by conventional methods andfurther oxidized using standard oxidizing agents to sulfone-aldehydeXLIII. Preferably, the oxidizing agent is metachloroperbenzoic acid.

[0533] Sulfone-aldehyde XLIII likewise is isolated by conventionalmethods and then cyclized to form the stereoisomeric benzothiepinesXLIVa and XLIVb. The cyclizing agent preferably is a base having a pHbetween about 8 and about 9. More preferably, the base is an alkoxidebase, and still more preferably, the base is potassium tert-butoxide.

[0534] The two oxidation steps of Scheme XI can be reversed withoutadversely affecting the overall reaction. Alcohol XLI can be oxidizedfirst to yield a sulfone-alcohol which is then oxidized to yield asulfone-aldehyde.

[0535] Scheme XII illustrates still another route tobenzothiepine-1,1-dioxides, particularly 3,3-dialkyl analogs, startingfrom the halobenzene L. Halobenzene L can be reacted with cyclic sulfateXL disclosed above to give the alcohol LI which can be oxidized to yieldthe sulfone-alcohol LII. Sulfone-alcohol LII itself can be furtheroxidized to give the sulfone-aldehyde LIII which can be cyclized to givea stereoisomeric mixture of benzothiepine LIVa and LIVb.

[0536] Halobenzene L (which is commercially available or can besynthesized from commercially available halobenzenes by one skilled inthe art) has the following formula:

[0537] wherein R⁵, R^(x), and q are as previously defined for thecompounds of formula I; R^(h) is a halogen such as chloro, bromo, fluoroor iodo; and R^(e) is an electron withdrawing group at the ortho or paraposition of the halobenzene, and is preferably a p-nitro or o-nitrogroup. Cyclic sulfate XL can be prepared as set forth in Scheme XI andcan have the following formula:

[0538] wherein R¹ and R² are as previously defined for the compounds offormula I. Preferably, R¹ and R² are alkyl; more preferably, they areselected from the group consisting of methyl, ethyl, propyl, isopropyl,n-butyl, iso-butyl, sec-butyl, tert-butyl, and pentyl; and still morepreferably, R¹ and R² are n-butyl.

[0539] In the process of Scheme XII, halobenzene L is initially reactedwith cyclic sulfate XL. This reaction preferably is conducted in anaprotic solvent such as dimethyl formamide or N:N-dimethylacetamide, andmore preferably, in dimethyl formamide. Although the reaction conditionssuch as temperature and time are not narrowly critical, the reactionpreferably is allowed to proceed at between about 70° C. and about 90°C. for about 8 to 12 hours. More preferably, the reaction temperature ismaintained at about 80° C. The reaction preferably employs anapproximately stoichiometric ratio of the starting materials, with aslight excess of cyclic sulfate XL being preferred. Reaction time andyield is improved by using about 1.1 to 1.3 equivalents of cyclicsulfate XL for each equivalent of halobenzene L present. Morepreferably, this ratio is about 1.1 equivalents of cyclic sulfate XL foreach equivalent of halobenzene L present.

[0540] In the process of the invention, halobenzene L also is treatedwith an abstracting agent. The abstracting agent can be added to thesolvent containing halobenzene L prior to, concurrently with, or afterthe addition of cyclic sulfate XL. Without being held to a particulartheory, it is believed the abstracting agent removes the halogen atomattached to the benzene ring of halobenzene L and replaces that atomwith a divalent sulfur atom. The resulting sulfur anion reacts withcyclic sulfate XL to open the sulfate ring. The sulfur anion of thehalobenzene then bonds with a terminal carbon atom of the open ringsulfate. The terminal group at the unbonded end of the open ring sulfateis the sulfate group. The abstracting agent generally is a dialkalimetal sulfide, and preferably it is dilithium sulfide. A slight excessof the abstracting agent is preferred relative to halobenzene L.Reaction time and yield is improved by using about 1.01 to 1.3equivalents of abstracting agent for each equivalent of halobenzene Lpresent. More preferably, this ratio is about 1.05 equivalents ofabstracting agent for each equivalent of halobenzene L present.

[0541] The sulfate group of the product of the reaction of thiophenolXVIIIA with cyclic sulfate XL is then removed, preferably by hydrolysis,to yield a mixture of an ester and alcohol LI. Suitable hydrolyzingagents include mineral acids, particularly hydrochloric acid andsulfuric acid. The ester is then converted to alcohol LI by treatmentwith an alkali metal hydroxide, preferably sodium hydroxide.

[0542] The several reactions involving halobenzene L, cyclic sulfate XL,the abstracting agent and the hydrolyzing agent can take place in situwithout the need to isolate any of the intermediates produced.

[0543] Alcohol LI is then isolated by conventional methods (for example,extraction with aqueous methyl salicylate) and oxidized using standardoxidizing agents to sulfone-alcohol LII. Preferably, the oxidizing agentis metachloroperbenzoic acid. The reaction is conducted in a suitableorganic solvent such as methylene chloride or chloroform.

[0544] Sulfone-alcohol LII is then isolated by conventional methods andfurther oxidized using standard oxidizing agents to sulfone-aldehydeLIII. Preferably, the oxidizing agent is sulfur trioxide or pyridiniumchlorochromate, and more preferably, it is pyridinium chlorochromate.The reaction is conducted in a suitable organic solvent such asmethylene chloride or chloroform.

[0545] Sulfone-aldehyde XLIII is then converted to the desiredbenzothiepine-1,1-dioxides according to the procedure previously setforth in Scheme XI.

[0546] The two oxidation steps can be reversed without adverselyaffecting the overall reaction. Alcohol XLI can be oxidized first toyield an aldehyde which is then oxidized to yield a sulfone-aldehyde.

[0547] Use of the cyclic sulfate reagent instead of a mesylate reagentin Schemes XI and XII improves the overall yield and avoids many of thepurification difficulties encountered relative to those reaction schemesproceeding through a mesylate intermediate. Overall yields aresignificantlyimproved when a cyclic sulfate is used instead of amesylate reagent. In addition, chromatographic separation of theintermediate product of the cyclic sulfate coupling step of the reactionis not necessary. For example, in Schemes XI and XII the intermediate isa water soluble alkali metal salt and the impurities can be removed byextraction with ether. The intermediate is then hydrolyzed to thedesired alcohol.

EXAMPLE CORRESPONDING TO SCHEME XI:

[0548] Step 1: Preparation of 2,2-dibutyl-1,3-propanediol:

[0549] Lithium aluminum hydride (662 ml, 1.2 equivalents, 0.66 mol) in662 mL of 1M THF was added dropwise to a stirred solution ofdibutyl-diethylmalonate (150 g, 0.55 mol) (Aldrich) in dry THF (700ml)while maintaining the temperature of the reaction mixture at betweenabout −20° C. to about 0° C. using an acetone/dry ice bath. The reactionmixture was then stirred at room temperature overnight. The reaction wascooled to −20° C. and 40 ml of water, 80 ml of 10% NaOH and 80 ml ofwater were successively added dropwise. The resulting suspension wasfiltered. The filtrate was dried over sodium sulphate and concentratedunder vacuum to give 98.4 g (yield 95%) of the diol as an oil. ProtonNMR, carbon NMR and MS confirmed the product.

[0550] Step 2: Dibutyl-cyclic-sulfite:

[0551] A solution of the dibutyl-diol of step 1 (103 g, 0.5478 mol) inanhydrous methylene chloride (500 ml) and triethylamine (221 g, 4equivalents, 2.19 mol) was stirred at 0° C. under nitrogen. Thionylchloride (97.78 g, 0.82 mol) was added dropwise to the mixture. Within 5minutes the solution turned to yellow and then to black when theaddition was completed within about half an hour. The reaction wascompleted within 3 hours (gas chromatography confirmed no startingmaterial was left). The mixture was washed with ice water twice, andbrine twice. The organic phase was dried over magnesium sulphate andconcentrated under vacuum to give 128 g (yield 100%) of thedibutyl-cyclic-sulfite as a black oil. NMR and MS were consistent withthe product.

[0552] Step 3: Dibutyl-cyclic sulfate:

[0553] To a solution of the dibutyl-cyclic-sulfite of step 2 (127.5 g,0.54 mol) in 600 ml acetonitrile and 500 ml of water cooled in an icebath under nitrogen was added ruthenium(III) chloride (1 g) and sodiumperiodate (233 g, 1.08 mol). The reaction was stirred overnight and thecolor of the solution turned black. Gas chromatography confirmed therewas no starting material left. The mixture was extracted once with 300ml of ether and three times with brine. The organic phase was dried overmagnesium sulphate and passed through celite. The filtrate wasconcentrated under vacuum and gave 133 g (yield 97.8%) of thedibutyl-cyclic-sulfate as an oil. Proton NMR, carbon NMR and MSconfirmed the product.

[0554] Step 4: 2-[(2-4′-fluorobenzyl-4-methylphenylthio)methyl]-2-butylhexanol:

[0555] A 60% oil dispersion of sodium hydride (0.27 g, 6.68 mmole) waswashed with hexane. The hexane was decanted and 20 ml of methoxyethylether was added to the washed sodium hydride and cooled in an ice bath.A mixture of diphenylmethane thiophenol (1.55 g, 6.68 mmole) in 10 ml ofmethoxyethyl ether was added dropwise over a period of 15 minutes. Amixture of the dibutyl-cyclic-sulfate of step 3 (2.17 g, 8.66 mmole) in10 ml of methoxyethyl ether was then added. The resulting mixture wasstirred for 30 minutes at 0° C. and 1 hour at room temperature undernitrogen. Gas chromatography confirmed there was no thiol left. Thesolvent was evaporated and washed with water and ether two times. Thewater layer was separated and 20 ml of 10% NaOH was added. This aqueousmixture was boiled for 30 minutes, cooled, acidified with 6N HCI, andboiled for 10 minutes. The mixture was cooled and extracted with ether.The organic layer was washed successively with water and brine, driedover magnesium sulphate, and concentrated under vacuum to give 2.47 g(yield 92.5%) of the hexanol as an oil. Proton NMR, C13-NMR and MSconfirmed the product.

[0556] Step 5:2-[(2-4′-fluorobenzyl-4-methylphenylthio)methyl]-2-butylhexanal:

[0557] To a solution of the hexanol of step 4 (2 g, 4.9 mmole) in 40 mlof methylene chloride cooled in an ice bath under nitrogen was addedpyridinium chlorochromate (2.18 g, 9.9 mmole). The reaction mixture wasstirred for 3 hours and filtered through silica gel. The filtrate wasconcentrated under vacuum to give 1.39 g (yield 70%) of the hexanal asan oil. Proton NMR, carbon NMR and MS confirmed the product.

[0558] Step 6: 2-[(2-4′-fluorobenzyl-4-methylphenylsulfonyl)methyl]-2-butylhexanal

[0559] To a solution of the hexanal of step 5 (0.44 g, 1.1 mmole) in 20ml of methylene chloride cooled by an ice bath under nitrogen was added70% metachloroperbenzoic acid (0.54 g, 2.2 mmole). The reaction mixturewas stirred for 18 hours and filtered.

[0560] The filtrate was washed successively with 10% NaOH(3×), water,and brine, dried over magnesium sulphate, and concentrated under vacuumto give 0.42 g (yield 90%) of the hexanal as an oil. Proton NMR, carbonNMR and MS confirmed the product.

[0561] Step 7:Cis-3,3-dibutyl-7-methyl-5-(4′-fluoro-phenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide:

[0562] A mixture of the hexanal of step 6 (0.37 g, 0.85 mmole) in 30 mlof anhydrous THF was stirred in an ice bath at a temperature of about 0°C. Potassium-tert-butoxide (102 mg, 0.85 mmole) was then added. After 3hours thin layer chromatography confirmed the presence of the productand a small amount of the starting material. The crude reaction mixturewas acidified with 10% HCl, extracted with ether, washed successivelywith water and brine, dried with MgSO₄, and concentrated under vacuum.This concentrate was purified by HPLC (10% EtOAc-Hexane). The firstfraction came as 0.1 g of the starting material in the form of an oil.The second fraction yielded 0.27 g (75% yield) of the desiredbenzothiepine as a white solid. Proton NMR, carbon NMR and MS confirmedthe product. (M+H=433).

EXAMPLE CORRESPONDING TO SCHEME XII

[0563] Step 1:2-[(2-4′-methoxybenzyl-4-nitrophenylthio)-methyl]-2-butylhexanol:

[0564] Chlorodiphenylmethane (10 g) was dissolved in 25 ml of DMF andlithium sulfide [1.75 g, 1.05 equivalents] was added. The solution colorchanged to red. The reaction mixture was heated at 80° C. overnight. Thesolution was cooled to 0° C. and dibutyl-cyclic-sulfate (9.9 g; preparedas set forth in Step 3 of the Scheme XI examples) in 10 ml of DMF wasadded and stirred at room temperature overnight. The solvent wasevaporated and washed successively with water and ether (three times).The water layer was separated and 40 ml of concentrated sulfuric acidwas added and the reaction mixture boiled overnight. The mixture wascooled and extracted with ethyl acetate. The organic layer was washedsuccessively with water and brine, dried over magnesium sulphate, andconcentrated under vacuum. The product was boiled with 3M of NaOH for 1hour. The mixture was cooled and extracted with ethyl acetate. Theorganic layer was washed successively with water and brine, dried overmagnesium sulphate, and concentrated under vacuum. The concentrate wasdissolved in methylene chloride, filtered through silica gel, elutedwith 20% ethyl acetate and hexane, and concentrated under vacuum to give11.9 g (yield 74%) of the hexanol as an oil. Proton NMR, C13-NMR and MSconfirmed the product.

[0565] To a solution of the hexanol of step 1 (6 g, 13 mmole) in 50 mlmethylene chloride cooled in ice bath under nitrogen was added 70% MCPBA(8.261 g, 33 mmole). The reaction was stirred for 18 hours at roomtemperature and filtered. The filtrate was washed successively with 10%NaOH (3×), water and brine, dried over magnesium sulphate, andconcentrated under vacuum. The concentrate was dissolved in methylenechloride, filtered through silica gel, eluted with 20% ethyl acetate andhexane, and concentrated under vacuum to give 5 g (yield 77.7%) of thehexanal as a white solid, MP 58-60° C. Proton NMR, C13-NMR and MSconfirmed the product.

EXAMPLE 1398

[0566]

[0567] To a solution of 6.0 g of dibutyl 4-fluorobenzene dialdehyde ofExample 1395 (14.3 mmol) in 72 mL of toluene and 54 mL of ethanol wasadded 4.7 g 3-nitrobenzeneboronic acid (28.6 mmol), 0.8 g of tetrakis(triphenylphosphine) palladium(0) (0.7 mmol) and 45 mL of a 2 M solutionof sodium carbonate in water. This heterogeneous mixture was refluxedfor three hours, then cooled to ambient temperature and partitionedbetween ethyl acetate and water. The organic layer was dried over MgSO₄and concentrated in vacuo. Purification by silica gel chromatography(Waters Prep-2000) using ethyl acetate/hexanes (25/75) gave 4.8 g (73%)of the title compound as a yellow solid. ¹H NMR (CDCl₃) d 0.88 (t,J=7.45 Hz, 6H), 0.99-1.38 (m, 8H), 1.62-1.75 (m, 2H), 1.85-2.00 (m, 2H),3.20 (s, 2H), 4.59 (s, 2H), 6.93 (dd, J=10.5 and 2.4 Hz, 1H), 7.15 (dt,J=8.4 and 2.85 Hz, lH), 7.46-7.59 (m, 2H), 8.05-8.16 (m, 3H), 9.40 (s,1H).

[0568] A solution of 4.8 g (10.4 mmol) of 2 in 500 mL THF was cooled to0° C. in an ice bath. 20 mL of a 1 M solution of potassium t-butoxidewas added slowly, maintaining the temperature at <5° C. Stirring wascontinued for 30 minutes, then the reaction was quenched with 100 mL ofsaturated ammonium chloride. The mixture was partitioned between ethylacetate and water; the organic layer was washed with brine, then dried(MgSO₄) and concentrated in vacuo. Purification by silica gelchromatography through a 100 ml plug using CH₂Cl₂ as eluent yielded 4.3g (90%) of 3 as a pale yellow foam. ¹H NMR (CDCl₃) d 0.93 (t, J=7.25 Hz,6H), 1.00-1.55 (m, 8H), 1.59-1.74 (m, 3H), 2.15-2.95 (m, 1H), 3.16(q_(AB), J_(AB)=15.0 Hz, AV =33.2 Hz, 2H), 4.17 (d, J=6.0 Hz, 1H), 5.67(s, 1H), 6.34 (dd, J=9.6 and 3.0 Hz, 1H), 7.08 (dt, J=8.5 and 2.9 Hz,1H), 7.64 (t, J=8.1 Hz, 1H), 7.81 (d, J=8.7 Hz, 1H), 8.13 (dd, J=9.9 and3.6 Hz, 1H), 8.23-8.30 (m, 1H), 8.44 (s, 1H). MS(FABH⁺) m/e (relativeintensity) 464.5 (100), 446.6 (65). HRMS calculated for M+H 464.1907.Found 464.1905.

[0569] To a cooled (0° C.) solution of 4.3 g (9.3 mmol) of 3 in 30 mlTHF contained in a stainless steel reaction vessel was added 8.2 gdimethyl amine (182 mmol). The vessel was sealed and heated to 110° C.for 16 hours. The reaction vessel was cooled to ambient temperature andthe contents concentrated in vacuo. Purification by silica gelchromatography (Waters Prep-2000) using an ethyl acetate/hexanesgradient (10-40% ethyl acetate) gave 4.0 g (88%) of 4 as a yellow solid.¹H NMR (CDCl₃) d 0.80-0.95 (m, 6H), 0.96-1.53 (m, 8H), 1.60-1.69 (m,3H), 2.11-2.28 (m, 1H), 2.79 (s, 6H), 3.09 (q_(AB), J_(AB)=15.0 Hz,DV=45.6 Hz, 2H), 4.90 (d, J=9.0 Hz, 1H), 5.65 (s, 1H), 5.75 (d, J=2.1Hz, 1H), 6.52 (dd, J=9.6 and 2.7 Hz, 1H), 7.59 (t, J=8.4 Hz, 1H), 7.85(d, J=7.80 Hz, 1H), 7.89 (d, J=9.0 Hz, 1H), 8.20 (dd, J=8.4 and 1.2 Hz,1H), 8.43 (s, 1H). MS(FABH+) m/e (relative intensity) 489.6 (100), 471.5(25). HRMS calculated for M+H 489.2423. Found 489.2456.

[0570] To a suspension of 1.0 g (2.1 mmol) of 4 in 100 ml ethanol in astainless steel Parr reactor was added 1 g 10% palladium on carbon. Thereaction vessel was sealed, purged twice with H₂, then charged with H₂(100 psi) and heated to 45° C. for six hours. The reaction vessel wascooled to ambient temperature and the contents filtered to remove thecatalyst. The filtrate was concentrated in vacuo to give 0.9 g (96%) of5. ¹H NMR (CDCl₃) d 0.80-0.98 (m, 6H), 1.00-1.52 (m, 10H), 1.52-1.69 (m,1H), 2.15-2.29 (m, 1H), 2.83 (s, 6H), 3.07 (q_(AB), J_(AB)=15.1 Hz, DV=44.2 Hz, 2H), 3.70 (s, 2H), 4.14 (s, 1H), 5.43 (s, 1H), 6.09 (d, J=2.4Hz, 1H), 6.52 (dd, J=12.2 and 2.6 Hz, 1H), 6.65 (dd, J=7.8 and 1.8 Hz,1H), 6.83 (s, 1H), 6.93 (d, J=7.50 Hz, 1H), 7.19 (t, J=7.6 Hz, 1H), 7.89(d, J=8.9 Hz, IH). MS(FABH+) m/e (relative intensity) 459.7 (100). HRMScalculated for M+H 459.2681. Found 459.2670.

[0571] Step 6. Preparation of 6

[0572] To a solution of 914 mg (2.0 mmol) of 5 in 50 ml THF was added800 mg (4.0 mmol) 5-bromovaleroyl chloride. Next was added 4 g (39.6mmol) TEA. The reaction was stirred 10 minutes, then partitioned betweenethyl acetate and brine. The organic layer was dried (MgSO₄) andconcentrated in vacuo. Purification by silica gel chromatography througha 70 ml MPLC column using a gradient of ethyl acetate(20-50%) in hexaneas eluent yielded 0.9 g (73%) of 6 as a pale yellow oil. ¹H NMR (CDCl₃)d 0.84-0.95 (m, 6H), 1.02-1.53 (m, 10H), 1.53-1.68 (m, 1H), 1.80-2.00(m, 4H), 2.12-2.26 (m, 4H), 2.38 (t, J=6.9 Hz, 2H), 2.80 (s, 6H), 3.07(q_(AB), J_(AB)=15.6 Hz, DV =40.4 Hz, 2H), 3.43 (t, J=6.9 Hz, 2H), 4.10(s, 1H), 5.51 (s, 1H), 5.95 (d, J=2.4 Hz, 1H), 6.51 (dd, J=9.3 and 2.7Hz, 1H), 7.28 (s, 1H), 7.32-7.41 (m, 2H), 7.78 (d, J 8.1 Hz, 1H), 7.90(d, J=9.0 Hz, 1H).

[0573] To a solution of 0.9 g (1.45 mmol) of 6 in 25 ml acetonitrile add18 g (178 mmol) TEA. Heat at 55° C. for 16 hours. The reaction mixturewas cooled to ambient temperature and concentrated in vacuo.Purification by reverse-phase silica gel chromatography (Waters DeltaPrep 3000) using an acetonitrile /water gradient containing 0.05% TFA(20-65% acetonitrile) gave 0.8 g (73%) of 7 as a white foam. ¹H NMR(CDCl₃) d 0.80-0.96 (m, 6H), 0.99-1.54 (m, 19H), 1.59-1.84 (m, 3H),2.09-2.24 (m, 1H), 2.45-2.58 (m, 2H), 2.81 (s, 6H), 3.09 (q_(AB),J_(AB)=15.6 Hz, DV=18.5 Hz, 2H), 3.13-3.31 (m, 8H), 4.16 (s, 1H), 5.44(s, 1H), 6.08 (d, J=1.8 Hz, 1H), 6.57 (dd, J=9.3 and 2.7 Hz, 1H), 7.24(t, J=7.5 Hz, 1H), 7.34 (t, J=8.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.74(s, 1H), 7.88 (d, J=9.0 Hz, 1H), 9.22 (s, 1H). HRMS calcd 642.4304;observed 642.4343.

EXAMPLE 1398A

[0574]

[0575] In an inert atmosphere, weigh out 68.3 gms phosphoruspentachloride (0.328mole Aldrich 15,777-5) into a 2-necked 500ml roundbottom flask. Fit flask with a N₂ inlet adapter and suba seal. Removefrom inert atmosphere and begin N₂ purge. Add 50mls anhydrouschlorobenzene (Aldrich 28,451-3) to the PCl₅ via syringe and beginstirring with magnetic stir bar.

[0576] Weigh out 60 gms 2-chloro-5-nitrobenzoic acid (0.298 mole Aldrich12,511-3). Slowly add to the chlorobenzene solution while under N₂purge. Stir at room temperature overnight. After stirring at roomtemperature for ˜20 hrs, place in oil bath and heat at 50C for 1 hr.Remove chlorobenzene by high vacuum. Wash residue with anhydrous hexane.Dry acid chloride wt=61.95 gms. Store in inert and dry atmosphere.

[0577] In inert atmosphere, dissolve acid chloride with 105 mlsanhydrous anisole (0.97 mole Aldrich 29,629-5). Place solution in a2-necked 500ml round bottom flask.

[0578] Weigh out 45.1 gms aluminum chloride (0.34 moles Aldrich29,471-3) and place in a solid addition funnel. Fit reaction flask withaddition funnel and a N₂ inlet adapter. Remove from inert atmosphere.Chill reaction solution with ice bath and begin N₂ purge. Slowly addAlC₃ to chilled solution. After addition is complete, allow to warm toroom temperature. Stir overnight .

[0579] Quench reaction by pouring into a solution of 300 mls 1N HCl andice. Stir 15 min. Extract twice with ether. Combine organic layers andextract twice with 2% NaOH, then twice with deionized H₂O. Dry withMgSO₄, filter and rotovap to dryness. Remove anisole by high vacuum.Crystalize product from 90% ethanol 10% ethyl acetate. Dry on vacuumline. Wt=35.2 gms. Yield 41%. Obtain NMR and mass spec (m/z=292).

[0580] Dissolve 38.10 gms (0.131 moles) of the benzophenone from step 1in 250 mls anhydrous methylene chloride. Place in a 3 liter flask fittedwith N₂ inlet, addition funnel and stopper. Stir with magnetic stir bar.Chill solution with ice bath.

[0581] Prepare a solution of 39.32 gms trifluoromethane sulfonic acid(0.262 mole Aldrich 15,853-4) and 170 mls anhydrous methylene chloride.Place in addition funnel and add dropwise to chilled solution under N₂.Stir 5 minutes after addition is complete.

[0582] Prepare a solution of 22.85 gms triethyl silane (0.197 moleAldrich 23,019-7) and 170mls anhydrous methylene chloride. Place inaddition funnel and add dropwise to chilled solution under N₂. Stir 5minutes after addition is complete.

[0583] Prepare a second solution of 39.32 gms trifluoromethane sulfonicacid and 170mls anhydrous methylene chloride. Place in addition funneland add dropwise to chilled solution under N₂. Stir 5 minutes afteraddition is complete.

[0584] Prepare a second solution of 22.85 gms triethyl silane and 170mls anhydrous methylene chloride. Place in addition funnel and adddropwise to chilled solution under N₂. After all additions are madeallow to slowly warm to room temperature overnight. Stir under N₂overnight.

[0585] Prepare 1300 mls saturated NaHCO₃ in a 4 liter beaker. Chill withice bath. While stirring vigorously, slowly add reaction mixture. Stirat chilled temperature for 30 min. Pour into a separatory funnel andallow separation. Remove organic layer and extract aqueous layer 2 timeswith methylene chloride. Dry organic layers with MgSO₄. Crystallize fromethanol. Dry on vacuum line. Dry wt=28.8 gms. Confirm by NMR and massspec (m/z=278).

[0586] Step 3

[0587] Dissolve 10.12 gms (0.036 moles) of product 2 with 200 mlsanhydrous DMSO. Place in a 500 ml round bottom flask with magnetic stirbar. Fit flask with water condenser, N₂ inlet, and stopper. Add 1.84 gmsLi₂S (0.040 moles Aldrich 21,324-1). Place flask in oil bath and heat at75° C. under N₂ overnight then cool to room temperature.

[0588] Weigh out 10.59 gms dibutyl mesylate (0.040 moles). Dissolve withanhydrous DMSO and add to reaction solution. Purge well with N₂, heatovernight at 80° C.

[0589] Cool to room temperature. Prepare 500 mls of 5% acetic acid in a2 liter beaker. While stirring, slowly add reaction mixture. Stir 30min. Extract with ether 3 times. Combine organic layers and extract withwater and sat'd NaCl. Dry organic layer with MgSO₄, filter and rotovapto dryness. Dry oil on vacuum line. Obtain pure product by columnchromatography using 95% hexane and 5% ethyl acetate as the mobilephase. Dry wt=7.8 gms. Obtain NMR and mass spec (m/z=444).

[0590] Dissolve 9.33 gms (0.021 moles) of product 3 with 120 mlsanhydrous methylene chloride. Place in a 250 ml round bottom flask withmagnetic stir bar. Fit flask with N₂ inlet and stopper. Chill solutionwith ice bath under N₂ purge. Slowly add 11.54 gms 3-chloroperbenzoicacid (0.0435 moles, Fluka 25800, ˜65%). After addition is complete warmto room temperature and monitor reaction by TLC. Reaction goes quicklyto the sulphoxide intermediate but takes 8 hrs to convert to thesulphone. Chill solution over night in freezer. Filter solid fromreaction, extract filtrate with 10% K₂CO₃. Extract aqueous layer twicewith methylene choride. Combine organic layers and dry with MgSO₄.Filter and rotovap to dryness. Obtain pure product by crystallizing fromethanol or isolating by column chromatography. Obtain NMR and mass spec(m/z=476).

[0591] Step 5

[0592] Reaction is done in a 300 ml stainless steel Parr stirred minireactor. Place 9.68 gms (0.0204 moles) of product 4 in reactor base. Add160 mls ethanol. For safety reasons next two compounds are added in a N₂atmosphere glove bag. In glove bag, add 15.3 mls formaldehyde (0.204moles, Aldrich 25,254-9, about 37 wt % in water) and 1.45 gms 10%Pd/Carbon (Aldrich 20,569-9). Seal reactor before removing from glovebag. Purge reactor three times with H₂. Heat to 55° C. under H₂. Runreaction at 200 psig H₂, 55° C., and a stir rate of 250 rpm. Runovernight under these conditions.

[0593] Cool reactor and vent H₂. Purge with N₂. Check progress of run byTLC. Reaction is a mixture of desired product and intermediate. Filterreaction mixture over a bed of celite washing well with ether. Rotovapand redissolve with ether. Extract with water. Dry organic layer withMgSO₄, filter and rotovap to dryness. Dry on vacuum line.

[0594] Charge reactor again with same amounts, seal reactor and runovernight under same conditions. After second run all of the materialhas been converted to the desired product. Cool and vent H₂ pressure.Purge with N₂. Filter over a bed of celite, washing well with ether.Rotovap to dryness. Dissolve with ether and extract with water. Dryorganic layer with MgSO₄, filter and rotovap to dryness. Dry on vacuumline. Obtain NMR and mass spec (m/z=474).

[0595] Step 6

[0596] Dissolve 8.97 gms (0.0189 mole) of product 5 with 135 mlsanhydrous THF. Place in a 250 ml round bottom flask with magnetic stirbar. Fit flask with N₂ inlet and stopper. Chill solution with ice/saltbath under N₂ purge. Slowly add 2.55 gms potassium t-butoxide (0.227mole Aldrich 15,667-1). After addition is complete, continue to stir at−10° C. monitoring by TLC. Once reaction is complete, quench by adding135 mls 10% HCl stirring 10 min. Extract three times with ether. Dryorganic layer with MgSO₄, filter and rotovap to dryness. Crystallizefrom ether. Obtain NMR and mass spec (m/z=474).

[0597] Step 7

[0598] Dissolve 4.67 gms (0.01 moles) of product 6 with 100 mlsanhydrous chloroform. Place in a 250 ml round bottom flask with magneticstir bar. Fit flask with N₂ inlet adapter and suba seal. Chill solutionwith dry ice /acetone bath under a N2 purge. Slowly add, via syringe,2.84 mls boron tribromide (0.03 moles Aldric h 20,220-7). Stir at coldtemperature for 15 min after addition then allow to warm to roomtemperature. Monitor reaction progress by TLC. Reaction is usuallycomplete in 3 hrs.

[0599] Chill solution with ice bath. Quench with 100 mls 10% K₂CO₃ whilestirring rapidly. Stir 10 min. then transfer to sep funnel and allowseparation. Remove aqueous layer. Extract organic layer once with 10%HCl, once H₂O, and once with saturated NaCl solution. Dry organic layerwith MgSO₄, filter and rotovap to dryness. Crystallize product fromether. Obtain NMR and mass spec (m/z=460).

[0600] Step 8

[0601] Weigh 0.38 gms NaH (9.57 mmoles Aldrich 19,923-0 60% disp. inmineral oil) in a 250 ml round bottom flask with magnetic stir bar. Fitflask with N₂ inlet and stopper. Chill NaH with ice bath and begin N₂purge.

[0602] Dissolve 4.0 gms (8.7 mmoles) of product 7 with 60 mls anhydrousDMF. Add to the cold NaH. Stir at cold temperature for 30 min. Add 1.33gms K₂CO₃ (9.57 mmoles Fisher P-208).

[0603] Dissolve 16.1 gms 1,2-bis-(2-iodoethoxy)ethane (43.5 mmolesAldrich 33,343-3) with 60 mls anhydrous DMF. Add to cold reactionmixture. Warm to room temperature then heat to 40° C. overnight underN₂.

[0604] Cleanup by diluting with ether and extracting sequentially with5% NaOH, H₂O, and saturated NaCl. Dry organic layer with MgSO₄, filterand dry. Obtain pure product by column chromatography using 75% hexane25% ethyl acetate as the mobile phase. Obtain NMR and mass spec(m/z=702).

[0605] Step 9

[0606] Dissolve 1.0 gms (1.43 mmoles) of product 8 with 10 mls anhydrousacetonitrile. Place in a 3 ounce Fischer-Porter pressure reaction vesselwith magnetic stir bar. Add 2.9 gms triethyl amine (28.6 mmoles Aldrich23,962-3) dissolved in 10 mls anhydrous acetonitrile. Purge well with N₂then close system Heat at 45° C. Monitor reaction by TLC. Reaction isusually complete in 48 hrs.

[0607] Perform cleanup by removing acetonitrile under vacuum. Redissolvewith anhydrous chloroform and precipitate quaternary ammonium salt withether. Repeat several times. Dry to obtain crystalline product. ObtainNMR and mass spec (m/z-675).

EXAMPLE 1399

[0608] Step 1. Preparation of 1

[0609] To a solution of 144 g of KOH (2560 mmol) in 1.1 L of DMSO wasadded 120 g of 2-bromobenzyl alcohol (641 mmol) slowly via additionfunnel. Then was added 182 g of methyliodide (80 mL, 1282 mmol) viaaddition funnel. Stirred at ambient temperature for fifteen minutes.Poured reaction contents into 1.0 L of water and extracted three timeswith ethyl acetate. The organic layer was dried over MgSO₄ andconcentrated in vacuo. Purified by silica-gel chromatography through a200 mL plug using hexanes (100%) as elutant yielded 103.2 g (80%) of 1as a clear colorless liquid. ¹H NMR (CDCl₃) d 3.39 (s, 3H), 4.42 (s,2H), 7.18-7.27 (m, 2H), 7.12 (d, J=7.45, 1H), 7.50 (s, 1H).

[0610] Step 2. Preparation of 2

[0611] To a cooled (−78° C.) solution of 95 g (472 mmol) of 1 in 1.5 LTHF was added 240 mL of 2.5 M n-butyl lithium (576 mmol). The mixturewas stirred for one hour, and then to it was added 180 g of zinc iodide(566 mmol) dissolved in 500 ml THF. The mixture was stirred thirtyminutes, allowed to warm to 5 C, cooled to −10° C. and to it was added 6g of Pd(PPh₃)₄ (5.2 mmol) and 125 g 2,5-difluorobenzoyl chloride (708mmol). The mixture was stirred at ambient temperature for 18 hoursandthen cooled to 10° C., quenched with water, partitioned between ethylacetate and water, and washed organic layer with 1N HCL and with 1NNaOH. The organic layer was dried over MgSO₄ and concentrated in vacuo.Purification by silica gel chromatography (Waters Prep-500) using 5%ethyl acetate/hexanes as elutant gave 53.6 g (43%) of 2 as an orangeoil. ¹H NMR (CDCl₃) d 3.40 (s, 3H), 4.51 (s, 2H), 7.12-7.26 (m, 3H),7.47 (t, J=7.50, 1H), 7.57 (d, J=7.45, 1H), 7.73 (d, J=7.45, 1H), 7.80(s, 1H).

[0612] Step 3. Preparation of 3

[0613] A solution of 53 g (202.3 mmol) of 2 and 11.2 g Li2S (242.8 mmol)in 250 mL DMF was heated to 100° C. for 18 hours. The reaction wascooled (0° C.) and 60.7 g of X (the cyclic sulfate compound of example1397) (242.8 rmmol) in 50 mL DMF was added. Stirred at ambienttemperature for 18 hours then condensed in vacuo. Added 1 L water toorganic residue and extracted twice with diethyl ether. Aqueous layeracidified (pH 1) and refluxed 2 days. Cooled to ambient temperature andextracted with methylene chloride, dried organic layer over MgSO₄ andcondensed in vacuo. Purification by silica gel chromatography (WatersPrep-500) using 10% ethyl acetate / hexanes as elutant gave 42.9 g (48%)of 3 as a yellow oil. ¹H NMR (CDCl₃) d 0.86 (t, J=7.25 Hz, 6H), 1.10 -1.26 (m, 12H), 2.83 (s, 2H), 3.32 (s, 2H), 3.40 (s, 3H), 4.48 (s, 3H),7.02 (dd, J=8.26 Hz and 2.82 Hz, 1H), 7.16 (dt, J=8.19 Hz and 2.82 Hz,1H), 7.45 (t, J=7.65 Hz, 1H), 7.56-7.61 (m, 2H), 7.69 (d, J=7.85 Hz,1H), 7.74 (s, 1H).

[0614] Step 4. Preparation of 4

[0615] To a cooled (−40° C.) solution of 42.9 g (96.2 mmol) of 3 in 200mL of methylene chloride was added 21.6 g trifluoromethane sulfonic acid(12.8 mL, 144 mmol) followed by the addition of 22.4 g triethyl silane(30.7 mL, 192.4 mmol). Stirred at −20° C. for two hours, quenched withwater and warmed to ambient temperature. Partitioned between methylenechloride and water, dried the organic layer over MgSO₄ and condensed invacuo. Purification by silica gel chromatography (Waters Prep-500) using10% ethyl acetate/ hexanes as elutant gave 24.2 g (60%)of 4 as a oil.¹NMR (CDCl₃) d 0.89 (t, J=7.05 Hz, 6H), 1.17 - 1.40 (m, 12H), 1.46 (t,J=5.84 Hz, 1H), 2.81 (s, 2H), 3.38 (s, 3H), 3.43 (d, J=5.23 Hz, 2H),4.16 (s, 2H), 4.42 (s, 2H), 6.80 (d, J=9.67 Hz, 1H), 6.90 (t, J=8.46 Hz,1H), 7.09 (d, J=7.45 Hz, 1H), 7.15 - 7.21 (m, 2H), 7.25 - 7.32 (m, 2H),7.42 (m, 1H).

[0616] Step 5. Preparation of 5

[0617] To a cooled (15-18° C.) solution of 24.2 g (55.8 inmol) of 4 in100 mL DMSO was added 31.2 g sulfur trioxide pyridine complex (195mmol). Stirred at ambient temperature for thirty minutes. Poured intocold water and extracted three times with ethyl acetate. Washed organicswith 5% HCl (300 mL) and then with brine (300 mL), dired organics overMgSO₄ and condensed in vacuo to give 23.1 g (96%) of 5 as a light brownoil. ¹H NMR (CDCl₃) d 0.87 (t, J=7.05 Hz, 6H), 1.01 - 1.32 (m, 8H),1.53 - 1.65 (m, 4H), 2.98 (s, 2H), 3.38 (s, 3H), 4.15 (s, 2H), 4.43 (s,2H), 6.81 (dd, J=9.66 Hz and 2.82 Hz, 1H), 6.91 (t, J=8.62 Hz, 1H), 7.07(d, J=7.46 Hz, 1H), 7.14 (s, 1H), 7.19 (d, J=7.65 Hz, 1H), 7.26 - 7.32(m, 1H), 7.42 (dd, J=8.66 Hz and 5.64 Hz, 1H), 9.40 (s, 1H).

[0618] To a cooled (0° C.) solution of 23.1 g (53.6 mmol) of 5 in 200 mLmethylene chloride was added 28.6 g meta cholorperoxy-benzoic acid(112.6 mmol). Stirred at ambient temperature for 24 hours. Quenched with100 mL 10% Na₂SO₃, partitioned between water and methylene chloride.Dried organic layer over MgSO₄ and condensed in vacuo to give 24.5 g(98%) of 6 as a light yellow oil. ¹H NMR (CDCl₃) d 0.86 - 1.29 (m, 14H),1.58 - 1.63 (m, 2H), 1.82 - 1.91 (m, 2H), 3.13 (s, 2H), 3.39 (s, 3H),4.44 (s, 2H), 4.50 (s, 2H), 6.93 (d, J=9.07 Hz, 1H), 7.10 - 7.33 (m,5H), 8.05 (s, 1H), 9.38 (s, 1H).

[0619] To a solution of 24.5 g (52.9 mmol) of 6 in 20 mL of THFcontained in a stainless steel reaction vessel was added 100 mL of a 2.0M solution of dimethyl amine and 20 mL of neat dimethyl amine. Thevessel was sealed and heated to 110° C. for 16 hours. The reactionvessel was cooled to ambient temperature and the contents concentratedin vacuo. Purification by silica gel chromatography (Waters Prep-500)using 15% ethyl acetate/hexanes gave 21.8 g (84%) of 7 as a clearcolorless oil. ¹NMR (CDCl₃) d 0.85 (t, J=7.25 Hz, 6H), 0.93 - 1.29 (m,8H), 1.49 - 1.59 (m, 2H), 1.70 -1.80 (m, 2H), 2.98 (s, 8H), 3.37 (s,3H), 4.41 (s, 2H), 4.44 (s, 2H), 6.42 (s, 1H), 6.58 (dd, J=9.0 Hz and2.61 Hz, 1H), 7.13 (d, J=7.45 Hz, 1H), 7.21 (s, 1H), 7.28 (t, J=7.85 Hz,1H), 7.82 (d, J=9.06 Hz, 1H), 9.36 (s, 1H).

[0620] A solution of 21.8 g (44.8 mmol) of 7 in 600 mL of THF was cooledto 0° C. 58.2 mL of a 1 M solution of potassium t-butoxide was addedslowly, maintaining the temperature at <5° C. Stirred for 30 minutes,then quenched with 50 mL of saturated ammonium chloride. The organiclayer was partitioned between ethyl acetate and water, dried over MgSO4and concentrated in vacuo. Purification by recrystalization from ˜10%ethyl acetate/hexanes gave 15.1 g of 8 as a white solid. The motherliquor was purified by silica gel chromatography (Waters Prep-500) using30% ethyl acetate/hexanes as the elutant to give 3.0 g of 8 as a whitesolid. MS (FABLi⁺) m/e 494.6. HRMS (EI⁺) calculated for M+H 487.2756.Found 487.2746.

[0621] A solution of 2.0 g (4.1 mmol) of 8 in 20 mL of methylenechloride was cooled to −60° C. 4.1 mL of a 1M solution of borontribromide was added. Stirred at ambient temperature for thirty minutes.Cooled reaction to ˜10° C. and quenched with 50 mL of water. The organiclayer was partitioned between methylene chloride and water, dried overMgSO₄ and concentrated in vacuo. Purification by recrystalization from50% ethyl acetate/methylene chloride gave 1.95 g (89%) of 9 as a whitesolid. MS (FABH⁺) m/e 537. HRMS (FAB) calculated for M 536.1834. Found536.1822.

[0622] A solution of 1.09 g (2.0 mmol) of 9 and 4.9 g (62 mmol) ofpyridine in 30 mL of acetonitrile was stirred at ambient temperature for18 hours. The reaction was concentrated in vacuo. Purification byrecrystallization from methanol/ diethyl ether gave 1.19 g (96%) of 10as an off white solid. MS (FAB⁺) m/e 535.5.

EXAMPLE 1400

[0623]

[0624] A 12-liter, 4-neck round-bottom flask was equipped with refluxcondenser, N₂ gas adaptor, mechanical stirrer, and an addition funnel.The system was purged with N₂. A slurry of sodium hydride (126.0 g/4.988mol) in toluene (2.5 L) was added, and the mixture was cooled to 6 C. Asolution of 4-fluorophenol (560.5 g/5.000 mol) in toluene (2.5 L) wasadded via addition funnel over a period of 2.5 h. The reaction mixturewas heated to reflux (100 C) for 1 h. A solution of 3-methoxybenzylchloride (783.0 g/5.000 mol) in toluene (750 mL) was added via additionfunnel while maintaining reflux. After 15 h. refluxing, the mixture wascooled to room temperature and poured into H₂0 (2.5 L). After 20 min.stirring, the layers were separated, and the organic layer was extractedwith a solution of potassium hydroxide (720 g) in MeOH (2.5 L). The MeOHlayer was added to 20% aqueous potassium hydroxide, and the mixture wasstirred for 30 min. The mixture was then washed 5 times with toluene.The toluene washes were extracted with 20% aq. KOH. All 20% aq. KOHsolutions were combined and acidified with concentrated HCl. The acidicsolution was extracted three times with ethyl ether, dried (MgSO₄),filtered and concentrated in vacuo. The crude product was purified byKugelrohr distillation to give a clear, colorless oil (449.0 g/39%yield). b.p.: 120-130 C/50 mtorrHg. ¹H NMR and MS [(M+H)⁺233] confirmeddesired structure.

[0625] A 12-liter, 3-neck round-bottom flask was fitted with mechanicalstirrer and N₂ gas adaptor. The system was purged with N₂.4-Fluoro-2-(3-methoxybenzyl)-phenol (455.5 g/1.961 mol) anddimethylformamide were added. The solution was cooled to 6 C, and sodiumhydride (55.5 g/2.197 mol) was added slowly. After warming to roomtemperature, dimethylthiocarbamoyl chloride (242.4 g/1.961 mol) wasadded. After 15 h, the reaction mixture was poured into H₂O (4.0 L), andextracted two times with ethyl ether. The combined organic layers werewashed with H₂O and saturated aqueous NaCl, dried (MgSO₄), filtered, andconcentrated in vacuo to give the product (605.3 g, 97% yield). ¹H NMRand MS [(M+H)⁺=320] confirm desired structure.

[0626] A 12-liter, round-bottom flask was equipped with N₂ gas adaptor,mechanical stirrer, and reflux condenser. The system was purged with N₂.4-Fluoro-2-(3-methoxybenzyl)-phenyldimethylthiocarbamate (605.3 g/1.895mol) and phenyl ether (2.0 kg) were added, and the solution was heatedto reflux for 2 h. The mixture was stirred for 64 h. at room temparatureand then heated to reflux for 2 h. After cooling to room temperature,MeOH (2.0 L) and THF (2.0 L) were added, and the solution was stirredfor 15 h. Potassium hydroxide (425.9 g/7.590 mol) was added, and themixture was heated to reflux for 4 h. After cooling to room temparature,the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0L), and extracted with H₂O. The aqueous extracts were combined,acidified with concentrated HCl, and extracted with ethyl ether. Theether extracts were dried (MgSO₄), filtered, and concentrated in vacuoto give an amber oil (463.0 g, 98% yield). ¹H NMR confirmed desiredstructure.

[0627] A 5-liter, 3-neck, round-bottom flask was equipped with N₂ gasadaptor and mechanical stirrer. The system was purged with N₂.4-Fluoro-2-(3-methoxybenzyl)-thiophenol (100.0 g/403.2mmol) and2-methoxyethyl ether (1.0 L) were added and the solution was cooled to 0C. Sodium hydride (9.68 g/383.2 mmol) was added slowly, and the mixturewas allowed to warm to room temparature, 2,2-Dibutylpropylene sulfate(110.89 g/443.6 mmol) was added, and the mixture was stirred for 64 h.The reaction mixture was concentrated by rotavap and dissolved in H₂O.The aqueous solution was washed with ethyl ether, and concentrated H₂SO₄was added. The aqueous solution was heated to reflux for 30 min, cooledto room temperature, and extracted with ethyl ether. The ether solutionwas dried (MgSO₄), filtered, and conc'd in vacuo to give an amber oil(143.94 g/85% yield). ¹H NMR and MS [(M +H)⁺=419] confirm the desiredstructure.

[0628] A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gasadaptor, and mechanical stirrer. The system was purged with N₂. Thecorresponding alcohol (143.94 g/343.8 mmol) and CH₂Cl₂ (1.0 L) wereadded and cooled to 0 C. Pyridinium chlorochromate (140.53 g/651.6 mmol)was added. After 6 h., CH₂Cl₂ was added. After 20 min, the mixture wasfiltered through silica gel, washing with CH₂Cl₂. The filtrate wasconcentrated in vacuo to give a dark yellow-red oil (110.6 g, 77%yield). ¹H NMR and MS [(M+H)⁺=417] confirm the desired structure.

[0629] Step 6

[0630] A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gasadaptor and mechanical stirrer. The system was purged with N₂. Thecorresponding sulfide (110.6 g/265.5 mmol) and CH₂Cl₂ (1.0 L) wereadded. The solution was cooled to 0 C, and 3-chloroperbenzoic acid(158.21 g/531.⁷ mmol) was added portionwise. After 30 min, the reactionmixture was allowed to warm to room temperature After 3.5 h, thereaction mixture was cooled to 0 C and filtered through a fine frittedfunnel. The filtrate was washed with 10% aqueous K₂CO₃. An emulsionformed which was extracted with ethyl ether. The organic layers werecombined, dried (MgSO₄), filtered, and concentrated in vacuo to give theproduct (93.2 g, 78% yield). ¹H NMR confirmed the desired structure.

[0631] Step 7

[0632] A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gasadaptor, mechanical stirrer, and a powder addition funnel. The systemwas purged with N₂. The corresponding aldehyde (93.2 g/208 mmol) and THF(1.0 L) were added, and the mixture was cooled to 0 C. Potassiumtert-butoxide (23.35 g/208.1 mmol) was added via addition funnel. After1 h, 10% aq/ HCl (1.0 L) was added. After 1 h, the mixture was extractedthree times with ethyl ether, dried (MgSO₄), filtered, and concentratedin vacuo. The crude product was purified by recryst. from 80/20hexane/ethyl acetate to give a white solid (32.18 g). The mother liquorwas concentrated in vacuo and recrystelized from 95/5 toluene/ethylacetate to give a white solid (33.60 g/combined yield: 71%). ¹H NMRconfirmed the desired product.

[0633] Step 8

[0634] A Fisher porter bottle was fitted with N₂ line and magneticstirrer. The system was purged with N₂. The correspondingfluoro-compound (28.lg/62.6 mmol) was added, and the vessel was sealedand cooled to −78 C. Dimethylamine (17.1 g/379 mmol) was condensed via aCO₂/acetone bath and added to the reaction vessel. The mixture wasallowed to warm to room temperature and was heated to 60 C. After 20 h,the reaction mixture was allowed to cool and was dissolved in ethylether. The ether solution was washed with H₂O, saturated aqueous NaCl,dried (MgSO₄), filtered, and concentrated in vacuo to give a white solid(28.5 g/96% yield). ¹H NMR confirmed the desired structure.

[0635] Step 9

[0636] A 250-mL, 3-neck, round-bottom flask was equipped with N₂ gasadaptor and magnetic stirrer. The system was purged with N₂. Thecorresponding methoxy-compound (6.62 g/14.0 mmol) and CHCl₃ (150 mL)were added. The reaction mixture was cooled to −78 C, and borontribromide (10.50 g/41.9 mmol) was added. The mixture was allowed towarm to room temperature After 4 h, the reaction mixture was cooled to 0C and was quenched with 10% K₂CO₃ (100 mL). After 10 min, the layerswere separated, and the aqueous layer was extracted two times with ethylether. The CHCl₃ and ether extracts were combined, washed with saturatedaqueous NaCl, dried (MgSO₄), filtered, and concentrated in vacuo to givethe product (6.27 g/98% yield). ¹H NMR confirmed the desired structure.

[0637] Step 10

[0638] In a 250 ml single neck round bottom Flask with stir bar place 2-diethylamineoethyl chloride hydochloride (fw 172.10 g/mole) Aldrich D8,720-1 (2.4 mmol,4.12 g), 34 ml dry ether and 34 ml of 1N KOH(aqueous).Stir 15 minutes and then separate by ether extraction and dry overanhydrous potassium carbonate.

[0639] In a separate 2-necked 250 ml round bottom flask with stir baradd sodium hydride (60% dispersion in mineral oil, 100 mg , 2.6 mmol)and 34 ml of DMF. Cool to ice temperature. Next add phenolproduct(previous step) 1.1 g (2.4 rnmilomoles in 5 ml DMF and the ethersolution prepared above. Heat to 40C for 3 days. The product whichcontained no starting material by TLC was diluted with ether andextracted with 1 portion of 5% NaOH, followed by water and then brine.The ether layer was dried over magnesium sulfate and isolated byremoving ether by rotary evaporation (1.3 gms) .The product may befurther purified by chromatography (SiO2 99% ethyl acetate/1% NH4OH at 5ml/min.). Isolated yield: 0.78 g (mass spec , and H1 NMR)

[0640] Step 11

[0641] The product from step 10 ( 0.57 gms, 1.02 millimole fw 558.83g/mole) and 1.6 gms iodoethane (10.02 mmol) was placed in 5 mlacetonitrile in a fischer-porter bottle and heated to 45 C for 3 days.The solution was evaporated to dryness and redissolved in 5 mls ofchloroform. Next ether was added to the chloroform solution and theresulting mixture was chilled. The desired product is isolated as aprecipitate 0.7272 gms. Mass spec M-I=587.9 , H NMR).

EXAMPLE 1401

[0642] Step 1

[0643] A 12-liter, 4-neck round-bottom flask was equipped with refluxcondenser, N₂ gas adaptor, mechanical stirrer, and an addition funnel.The system was purged with N₂. A slurry of sodium hydride (126.0 g/4.988mol) in toluene (2.5 L) was added, and the mixture was cooled to 6 C. Asolution of 4-fluorophenol (560.5 g/5.000 mol) in toluene (2.5 L) wasadded via addition funnel over a period of 2.5 h. The reaction mixturewas heated to reflux (100 C) for 1 h. A solution of 3-methoxybenzylchloride (783.0 g/5.000 mol) in toluene (750 mL) was added via additionfunnel while maintaining reflux. After 15 h. refluxing, the mixture wascooled to room temperature and poured into H₂O (2.5 L). After 20 min.stirring, the layers were separated, and the organic layer was extractedwith a solution of potassium hydroxide (720 g) in MeOH (2.5 L). The MeOHlayer was added to 20% aqueous potassium hydroxide, and the mixture wasstirred for 30 min. The mixture was then washed 5 times with toluene.The toluene washes were extracted with 20% aq. KOH. All 20% aqueous KOHsolutions were combined and acidified with concentrated HCl. The acidicsolution was extracted three times with ethyl ether, dried over MgSO₄,filtered and concentrated in vacuo. The crude product was purified byKugelrohr distillation to give a clear, colorless oil (449.0 g/39%yield). b.p.: 120-130 C/50 mtorrHg. ¹H NMR and MS [(M+H)⁺=233] confirmeddesired structure.

[0644] Step 2

[0645] A 12-liter, 3-neck round-bottom flask was fitted with mechanicalstirrer and N₂ gas adaptor. The system was purged with N₂.4-Fluoro-2-(3-methoxybenzyl)-phenol (455.5 g/1.961 mol) anddimethylformamide were added. The solution was cooled to 6 C, and sodiumhydride (55.5 g/2.197 mol) was added slowly. After warming to roomtemperature, dimethylthiocarbamoyl chloride (242.4 g/1.961 mol) wasadded. After 15 h, the reaction mixture was poured into H₂O (4.0 L), andextracted two times with ethyl ether. The combined organic layers werewashed with H₂O and saturated aqueous NaCl, dried over MgSO₄, filtered,and concentrated in vacuo to give the product (605.3 g, 97% yield). ¹HNMR and MS [(M+H)⁺=320] confirm desired structure.

[0646] Step 3

[0647] A 12-liter, round-bottom flask was equipped with N₂ gas adaptor,mechanical stirrer, and reflux condenser. The system was purged with N₂.4-Fluoro-2-(3-methoxybenzyl)-phenyldimethylthiocarbamate (605.3 g/1.895mol) and phenyl ether (2.0 kg) were added, and the solution was heatedto reflux for 2 h. The mixture was stirred for 64 h. at room temperatureand then heated to reflux for 2 h. After cooling to room temperature,MeOH (2.0 L) and THF (2.0 L) were added, and the solution was stirredfor 15 h. Potassium hydroxide (425.9 g/7.590 mol) was added, and themixture was heated to reflux for 4 h. After cooling to room temperature,the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0L), and extracted with H₂O. The aqueous extracts were combined,acidified with conc. HCl, and extracted with ethyl ether. The etherextracts were dried (MgSO₄), filtered, and concentrated in vacuo to givean amber oil (463.0 g, 98% yield). ¹H NMR confirmed desired structure.

[0648]

[0649] Step 4

[0650] A 5-liter, 3-neck, round-bottom flask was equipped with N₂ gasadaptor and mechanical stirrer. The system was purged with N₂.4-Fluoro-2-(3-methoxybenzyl)-thiophenol (100.Og/403.2 mmol) and2-methoxyethyl ether (1.0 L) were added and the solution was cooled to 0C. Sodium hydride (9.68 g/383.2 mmol) was added slowly, and the mixturewas allowed to warm to room temperature 2,2-Dibutylpropylene sulfate(110.89 g/443.6 mmol) was added, and the mixture was stirred for 64 h.The reaction mixture was concentrated by rotavap and dissolved in H₂O.The aqueous solution was washed with ethyl ether, and conc. H₂SO₄ wasadded. The aqueous solution was heated to reflux for 30 min, cooled toroom temperature, and extracted with ethyl ether. The ether solution wasdried (MgSO₄), filtered, and concentrated in vacuo to give an amber oil(143.94 g/85% yield). ¹H NMR and MS [(M+H)⁺=419] confirm the desiredstructure.

[0651] Step 5

[0652] A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gasadaptor, and mechanical stirrer. The system was purged with N₂. Thecorresponding alcohol (143.94 g/343.8 mmol) and CH₂Cl₂ (1.0 L) wereadded and cooled to 0 C. Pyridinium chlorochromate (140.53 g/651.6 mmol)was added. After 6 h., CH₂Cl₂ was added. After 20 min, the mixture wasfiltered through silica gel, washing with CH₂Cl₂. The filtrate wasconcentrated in vacuo to give a dark yellow-red oil (110.6 g, 77%yield). ¹H NMR and MS [(M+H)⁺=417] confirm the desired structure.

[0653] Step 6

[0654] A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gasadaptor and mechanical stirrer. The system was purged with N₂. Thecorresponding sulfide (110.6 g/265.5 mmol) and CH₂Cl₂ (1.0 L) wereadded. The solution was cooled to 0 C, and 3-chloroperbenzoic acid(158.21 g/531.⁷ mmol) was added portionwise. After 30 min, the reactionmixture was allowed to warm to room temperature After 3.5 h, thereaction mixture was cooled to 0 C and filtered through a fine frittedfunnel. The filtrate was washed with 10% aqueous K₂CO₃. An emulsionformed which was extracted with ethyl ether. The organic layers werecombined, dried (MgSO₄), filtered, and concentrated in vacuo to give theproduct (93.2 g, 78% yield). ¹H NMR confirmed the desired structure.

[0655] Step 7

[0656] A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gasadaptor, mechanical stirrer, and a powder addition funnel. The systemwas purged with N₂. The corresponding aldehyde (93.2 g/208 mmol) and THF(1.0 L) were added, and the mixture was cooled to 0 C. Potassiumtert-butoxide (23.35 g/208.lmmol) was added via addition funnel. After 1h, 10% aq/ HCl (1.0 L) was added. After 1 h, the mixture was extractedthree times with ethyl ether, dried (MgSO₄), filtered, and concentratedin vacuo. The crude product was purified by recrystallized from 80/20hexane/ethyl acetate to give a white solid (32.18 g). The mother liquorwas concentrated in vacuo and recrystallized from 95/5 toluene/ethylacetate to give a white solid (33.60 g, combined yield: 71%). ¹H NMRconfirmed the desired product.

[0657] Step 8

[0658] A Fisher porter bottle was fitted with N₂ line and magneticstirrer. The system was purged with N₂. The correspondingfluoro-compound (28.lg/62.6 mmol) was added, and the vessel was sealedand cooled to −78 C. Dimethylamine (17.1 g/379 mmol) was condensed via aCO₂/acetone bath and added to the reaction vessel. The mixture wasallowed to warm to room temperature and was heated to 60 C. After 20 h,the reaction mixture was allowed to cool and was dissolved in ethylether. The ether solution was washed with H₂O, saturated aqueous NaCl,dried over MgSO₄, filtered, and concentrated in vacuo to give a whitesolid (28.5 g/96% yield). ¹H NMR confirmed the desired structure.

[0659] Step 9

[0660] A 250-mL, 3-neck, round-bottom flask was equipped with N₂ gasadaptor and magnetic stirrer. The system was purged with N₂. Thecorresponding methoxy-compound (6.62 g/14.0 mmol) and CHCl₃ (150 mL)were added. The reaction mixture was cooled to −78 C, and borontribromide (10.50 g/41.9 mmol) was added. The mixture was allowed towarm to room temperature After 4 h, the reaction mixture was cooled to 0C and was quenched with 10% K₂CO₃ (100 mL). After 10 min, the layerswere separated, and the aqueous layer was extracted two times with ethylether. The CHCl₃ and ether extracts were combined, washed with saturatedaqueous NaCl, dried over MgSO₄, filtered, and concentrated in vacuo togive the product (6.27 g/98% yield). ¹H NMR confirmed the desiredstructure.

[0661] Step 10

[0662] In a 250 ml single neck round bottom flask with stir bar place 2-diethylamineoethyl chloride hydochioride (fw 172.10 g/mole) Aldrich D8,720-1 (2.4 millimoles, 4.12 g), 34 ml dry ether and 34 ml of 1N KOH(aqueous) . Stir 15 minutes and then separate by ether extraction anddry over anhydrous potassium carbonate.

[0663] In a separate 2-necked 250 ml round bottom flask with stir baradd sodium hydride (60% dispersion in mineral oil, 100 mg, (2.6 mmol)and 34 ml of DMF. Cool is to ice temperature. Next add phenol product(previous step) 1.1 g (2.4 mmol in 5 ml DMF and the ether solutionprepared above. Heat to 40C for 3 days. The product which contained nostarting material by TLC was diluted with ether and extracted with 1portion of 5% NaOH, followed by water and then brine. The ether layerwas dried over Magnesium sulfate and isolated by removing ether byrotary evaporation (1.3 gms). The product may be further purified bychromatography (silica 99% ethyl acetate/1% NH40H at 5 ml/min.).Isolated yield: 0.78 g (mass spec , and Hi NMR)

[0664] Step 11

[0665] The product from step 10 (0.57 gms, 1.02 millimole fw 558.83g/mole) and iodoethane (1.6 gms (10.02 mmilimoles)was place in 5 mlacetonitrile in a Fischer-Porter bottle and heated to 45 C for 3 days.The solution was evaporated to dryness and redissolved in 5 mls ofchloroform. Next ether was added to the chloroform solution and theresulting mixture was chilled. The desired product is isolated as aprecipitate 0.7272 gms. Mass spec M-I =587.9, ¹H NMR).

EXAMPLE 1402

[0666]

[0667](4R-cis)-5-[[5-[4-[3,3-Dibutyl-7-(dirmethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyl]thio]-1H-tetrazole-1-aceticacid

[0668] Step 1. Preparation of4-fluoro-2-((4-methoxyphenyl)methyl)-phenol

[0669] To a stirred solution of 23.66 g of 95% sodium hydride (0.94 mol)in 600 mL of dry toluene was added 100.0 g of 4-fluorophenol (0.89 mol)at 0° C. The mixture was stirred at 90° C. for 1 hour until gasevolution stopped. The mixture was cooled down to room temperature and asolution of 139.71 g of 3-methoxybenzyl chloride (0.89 mol) in 400 mL ofdry toluene was added. After refluxing for 24 hours, the mixture wascooled to room temperature and quenched with 500 mL of water. Theorganic layer was separated, dried over MgSO₄, and concentrated underhigh vacuum. The remaining starting materials were removed bydistillation. The crude dark red oil was filtered through a layer of 1 Lof silica gel with neat hexane to yield 53.00 g (25.6%) of the productas a pink solid: ¹H NMR (CDCl₃) δ 3.79 (s, 3H), 3.90 (s, 2H), 4.58 (s,1H), 6.70-6.74 (m, 1H), 6.79-6.88 (m, 4H), 7.11-7.16 (m, 2H).

[0670] Step 2. Preparation of4-fluoro-2-((4-methoxyphenyl)methyl)-thiophenol

[0671] Step 2a. Preparation of thiocarbamate

[0672] To a stirred solution of 50.00 g (215.30 mmol) of4-fluoro-2-((4-methoxyphenyl)methyl)-phenol in 500 mL of dry DMF wasadded 11.20 g of 60% sodium hydride dispersion in mineral oil (279.90mmol) at 2° C. The mixture was allowed to warm to room temperature and26.61 g of dimethylthiocarbamoyl chloride (215.30 mmol) was added. Thereaction mixture was stirred at room temperature overnight. The mixturewas quenched with 100 mL of water in an ice bath. The solution wasextracted with 500 mL of diethyl ether. The ether solution was washedwith 500 mL of water and 500 mL of brine. The ether solution was driedover MgSO₄ and stripped to dryness. The crude product was filteredthrough a plug of 500 mL silica gel using 5% ethyl acetate/hexane toyield 48.00 g (69.8%) of the product as a pale white solid: ¹NMR (CDCl₃)δ 3.21 (s, 3H), 3.46 (s, 3H), 3.80 (s, 3H), 3.82 (s, 2H), 6.78-6.86 (m,3H), 6.90-7.00 (m, 2H), 7.09 (d, J=8.7 Hz, 2H).

[0673] Step 2b. Rearrangement and hydrolysis of thiocarbamate to4-fluoro-2-((4-methoxyphenyl)methyl)-thiophenol

[0674] A stirred solution of 48.00 g (150.29 mmol) of thiocarbamate(obtained from Step 2a) in 200 mL of diphenyl ether was refluxed at 270°C. overnight. The solution was cooled down to room temperature andfiltered through 1 L of silica gel with 2 L of hexane to remove phenylether. The rearrangement product was washed with 5% ethyl acetate/hexaneto give 46.00 g (95.8%) of the product as a pale yellow solid: ¹NMR(CDCl₃) δ 3.02 (s, 3H), 3.10 (s, 3H), 3.80 (s, 3H), 4.07 (s, 2H),6.82-6.86 (m, 3H), 6.93 (dt, J=8.4 Hz, 2.7 Hz, 1H), 7.08 (d, J=8.7 Hz,2H), 7.49 (dd, J=6.0 Hz, 8.7 Hz, 1H).

[0675] To a solution of 46.00 g (144.02 mmol) of the rearrangementproduct (above) in 200 mL of methanol and 200 mL of THF was added 17.28g of NaOH (432.06 mmol). The mixture was refluxed under nitrogenovernight. The solvents were evaporated off and 200 mL of water wasadded. The aqueous solution was washed with 200 mL of diethyl ethertwice and placed in an ice bath. The aqueous mixture was acidified to pH6 with concentrated HCl solution. The solution was extracted with 300 mLof diethyl ether twice. The ether layers were combined, dried over MgSO₄and stripped to dryness to afford 27.00 g (75.5%) of the product as abrown oil: ¹NMR (CDCl₃) δ 3.24 (s, 1H), 3.80 (s, 3H), 3.99 (s, 2H),6.81-6.87 (m, 4H), 7.09 (d, J=8.7 Hz, 2H), 7.27-7.33 (m, 1H).

[0676] Step 3. Preparation of dibutyl cyclic sulfate

[0677] Step 3a. Preparation of 2,2-dibutyl-1,3-propanediol.

[0678] To a stirred solution of di-butyl-diethylmalonate (Aldrich) (150g, 0.55 mol in dry THF (700 ml) in an acetone/dry ice bath was added LAH(1 M THF) 662 ml (1.2 eq., 0.66 mol) dropwise maintaining thetemperature between −20 to 0° C. The reaction was stirred at RTovernight. The reaction was cooled to −20° C. and 40 ml of water, and 80mL of 10% NaOH and 80 ml of water were added dropwise. The resultingsuspension was filtered. The filtrate was dried over sodium sulphate andconcentrated in vacuo to give diol 98.4 g (yield 95%) as an oil. MSspectra and proton and carbon NMR spectra were consistent with theproduct.

[0679] Step 3b. Preparation of dibutyl cyclic sulfite

[0680] A solution of 2,2-dibutyl-1,3-propanediol (103 g, 0.548 mol,obtained from Step 3a) and triethylamine (221 g, 2.19 mol) in anhydrousmethylene chloride (500 ml) was stirred at 0° C. under nitrogen. To themixture, thionyl chloride (97.8 g, 0.82 mol) was added dropwise andwithin 5 min the solution turned yellow and then black when the additionwas completed within half an hour. The reaction mixture was stirred for3 hrs. at 0° C. GC showed that there was no starting material left. Themixture was washed with ice water twice then with brine twice. Theorganic phase was dried over magnesium sulfate and concentrated undervacuum to give 128 g (100%) of the dibutyl cyclic sulfite as a blackoil. Mass spectrum (MS) was consistent with the product.

[0681] Step 3c. Oxidation of dibutyl cyclic sulfite to dibutyl cyclicsulfate

[0682] To a solution of the dibutyl cyclic sulfite (127.5 g , 0.54 mol,obtained from Step 3b) in 600 ml acetonitrile and 500 ml of water cooledin an ice bath under nitrogen was added ruthenium (III) chloride (1 g)and sodium periodate (233 g, 1.08 mol). The reaction was stirredovernight and the color of the solution turned black. GC showed thatthere was no starting material left. The mixture was extracted with 300ml of ether and the ether extract was washed three times with brine. Theorganic phase was dried over magnesium sulfate and passed throughcelite. The filtrate was concentrated under vacuum and to give 133 g(97.8%) of the dibutyl cyclic sulfate as an oil. Proton and carbon NMRand MS were consistent with the product.

[0683] Step 4. Preparation of aryl-3-hydroxypropylsulfide

[0684] To a stirred solution of 27.00 g (108.73 mmol) of4-fluoro-2-((4-methoxyphenyl)methyl)thiophenol (obtained from Step 2) in270 mL of diglyme was added 4.35 g of 60% sodium hydride dispersion inmineral oil (108.73 mmol) at 0° C. After gas evolution ceased, 29.94 g(119.60 mmol) of the dibutyl cyclic sulfate (obtained from Step 3c) wasadded at 0C and stirred for 10 minutes. The mixture was allowed to warmup to room temperature and stirred overnight. The solvent was evaporatedand 200 mL of water was added. The solution was washed with 200 mL ofdiethyl ether and added 25 mL of concentrated sulfuric acid to make a2.0 M solution that was refluxed overnight. The solution was extractedwith ethyl acetate and the organic solution was dried over MgSO₄ andconcentrated in vacuo. The crude aryl-3-hydroxypropylsulfide waspurified by silica gel chromatography (Waters Prep 500) using 8% ethylacetate/hexane to yield 33.00 g (72.5%) of the product as a light brownoil: ¹NMR (CDCl₃) δ 0.90 (t, J=7.1 Hz, 6H), 1.14-1.34 (m, 12H), 2.82 (s,2H), 3.48 (s, 2H), 3.79 (s, 3H), 4.10 (s, 2H), 6.77-6.92 (m, 4H), 7.09(d, J 8.7 Hz, 2H), 7.41 (dd, J=8.7 Hz, 5.7 Hz, H).

[0685] Step 5. Preparation of enantiomerically-enrichedaryl-3-hydroxypropylsulfoxide

[0686] To a stirred solution of 20.00 g (47.78 mmol) ofaryl-3-hydroxypropylsulfide (obtained from Step 4) in 1 L of methylenechloride was added 31.50 g of 96%(1R)-(−)-(8,8-dichloro-10-camphor-sulfonyl)oxaziridine (100.34 mmol,Aldrich) at 2° C. After all the oxaziridine dissolved the mixture wasplaced into a −30° C. freezer for 72 hours. The solvent was evaporatedand the crude solid was washed with 1 L of hexane. The white solid wasfiltered off and the hexane solution was concentrated in vacuo. Thecrude oil was purified on a silica gel column (Waters Prep 500) using15% ethyl acetate/hexane to afford 19.00 g (95%) of theenantiomerically-enriched aryl-3-hydroxypropylsulfoxide as a colorlessoil: ¹H NMR (CDCl₃) δ 0.82-0.98 (m, 6H), 1.16-1.32 (m, 12H), 2.29 (d,J=13.8 Hz, 1H), 2.77 (d, J=13.5 Hz, 1H), 3.45 (d, J=12.3 Hz, 1H), 3.69(d, J=12.3 Hz, 1H), 3.79 (s, 3H), 4.02 (q, J=15.6 Hz, 1H), 6.83-6.93 (m,3H), 7.00 (d, J=8.1 Hz, 2H), 7.18-7.23 (m, 1H), 7.99-8.04 (m, 1H).Enantiomeric excess was determined by chiral HPLC on a (R,R)-Whelk-Ocolumn using 5% ethanol/hexane as the eluent. It showed to be 78% e.e.with the first eluting peak as the major product.

[0687] Step 6. Preparation of enantiomerically-enrichedaryl-3-propanalsulfoxide

[0688] To a stirred solution of 13.27 g of triethylamine (131.16 mmol,Aldrich) in 200 mL dimethyl sulfoxide were added 19.00 g (43.72 mmol) ofenantiomerically-enriched aryl-3-hydroxypropylsulfoxide (obtained fromStep 5) and 20.96 g of sulfur trioxide-pyridine (131.16 mmol, Aldrich)at room temperature. After the mixture was stirred at room temperaturefor 48 hours, 500 mL of water was added to the mixture and stirredvigorously. The mixture was then extracted with 500 mL of ethyl acetatetwice. The ethyl acetate layer was separated, dried over MgSO₄, andconcentrated in vacuo. The crude oil was filtered through 500 mL ofsilica gel using 15% ethyl acetate/hexane to give 17.30 g (91%) of theenantiomerically-enriched aryl-3-propanalsulfoxide as a light orangeoil: ¹H NMR (CDCl₃) δ 0.85-0.95 (m, 6H), 1.11-1.17 (m, 4H), 1.21-1.39(m, 4H), 1.59-1.76 (m, 4H), 1.89-1.99 (m, 1H), 2.57 (d, J=14.1 Hz, 1H),2.91 (d, J=13.8 Hz, 1H), 3.79 (s, 3H), 3.97 (d, J=15.9 Hz, 1H), 4,12 (d,J=15.9 Hz, 1H), 6.84-6.89 (m, 3H), 7.03 (d, J=8.4 Hz, 2H), 7.19 (dt,J=8.4 Hz, 2.4 Hz, 1H), 8.02 (dd, J=8.7 Hz, 5.7 Hz, 1H), 9.49 (s, 1H).

[0689] Step 7. Preparation of the enantiomerically-enrichedtetrahydrobenzothiepine-l-oxide (4R,5R)

[0690] To a stirred solution of 17.30 g (39.99 mmol) ofenantiomerically-enriched aryl-3-propanalsulfoxide (obtained from Step6) in 300 mL of dry THF at −15° C. was added 48 mL of 1.0 M potassiumt-butoxide in THF (1.2 equivalents) under nitrogen. The solution wasstirred at −15° C. for 4 hours. The solution was then quenched with 100mL of water and neutralized with 4 mL of concentrated HCl solution at 0°C. The THF layer was separated, dried over MgSO₄, and concentrated invacuo. The enantiomerically-enriched tetrahydrobenzothiepine-1-oxide(4R,5R) was purified by silica gel chromatography (Waters Prep 500)using 15% ethyl acetate/hexane to give 13.44 g (77.7%) of the product asa white solid: ¹NMR (CDCl₃) δ 0.87-0.97 (m, 6H), 1.16-1.32 (m, 4H),1.34-1.48 (m, 4H), 1.50-1.69 (m, 4H), 1.86-1.96 (m, 1H), 2.88 (d, J=13.0Hz, 1H), 3.00 (d, J=13.0 Hz, 1H), 3.85 (s, 3H), 4.00 (s, 1H), 4.48 (s,IH), 6.52 (dd, J=9.9 Hz, 2.4 Hz, 1H), 6.94 (d, J=9 Hz, 2H), 7.13 (dt,J=8.4 Hz, 2.4 Hz, 1H), 7.38 (d, J=8.7 Hz, 2H), 7.82 (dd, J=8.7 Hz, 5.7Hz, 1H).

[0691] Step 8. Preparation of enantiomerically-enrichedtetrahydrobenzothiepine-1,1-dioxide (4R,SR)

[0692] To a stirred solution of 13.44 g (31.07 mmol) ofenantiomerically-enriched tetrahydrobenzothiepine-1-oxide (obtained fromStep 7) in 150 mL of methylene chloride was added 9.46 g of 68%m-chloroperoxybenzoic acid (37.28 mmol, Sigma) at 0° C. After stirringat 0 ° C. for 2 hours, the mixture was allowed to warm up to roomtemperature and stirred for 4 hours. 50 mL of saturated Na₂SO₃ was addedinto the mixture and stirred for 30 minutes. The solution was thenneutralized with 50 mL of saturated NaHCO₃ solution. The methylenechloride layer was separated, dried over MgSO₄, and concentrated invacuo to give 13.00 g (97.5%) of the enantiomerically-enrichedtetrahydrobenzothiepine-1,1-dioxide (4R,5R) as a light yellow solid:¹NMR (CDCl₃) δ 0.89-0.95 (m, 6H), 1.09-1.42 (m, 12H), 2.16-2.26 (m, 1H),3.14 (q, J=15.6 Hz, 1H), 3.87 (s, 3H), 4.18 (s, 1H), 5.48 (s, 1H), 6.54(dd, J=10.2 Hz, 2.4 Hz, 1H), 6.96-7.07 (m, 3H), 7.40 (d, J=8.1 Hz, 2H),8.11 (dd, J=8.6 Hz, 5.9 Hz, 1H).

[0693] Step 9. Preparation of enantiomerically-enriched7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (4R,5R)

[0694] To a solution of 13.00 g (28.98 mmol) ofenantiomerically-enriched tetrahydrobenzothiepine-1,1-dioxide (obtainedfrom Step 8) in 73 mL of dimethylamine (2.0 M in THF, 146 mmol) in aParr Reactor was added about 20 mL of neat dimethylamine. The mixturewas sealed and stirred at 110° C. overnight, and cooled to ambienttemperature. The excess dimethylamine was evaporated. The crude oil wasdissolved in 200 mL of ethyl acetate and washed with 100 mL of water,dried over MgSO₄ and concentrated in vacuo. Purification on a silica gelcolumn (Waters Prep 500) using 20% ethyl acetate/hexane gave 12.43 g(90.5%) of the enantiomerically-enriched7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (4R,5R) as acolorless solid: ¹H NMR (CDCl₃) δ 0.87-0.93 (m, 6H), 1.10-1.68 (m, 12H),2.17-2.25 (m, 1H), 2.81 (s, 6H), 2.99 (d, J=15.3 Hz, 1H), 3.15 (d,J=15.3 Hz, 1H), 3.84 (s, 3H), 4.11 (d, J=7.5 Hz, 1H), 5.49 (s, 1H), 5.99(d, J=2.4 Hz, 1H), 6.51 (dd, J=8.7 Hz, 2.4 Hz, 1H), 6.94 (d, J=8.7 Hz,2H), 7.42 (d, J=8.4 Hz, 2H), 7.90 (d, J=8.7 Hz, 1H). The product wasdetermined to have 78% e.e. by chiral HPLC on a Chiralpak AD columnusing 5% ethanol/hexane as the eluent. Recrystallization of this solidfrom ethyl acetate/hexane gave 1.70 g of the racemic product. Theremaining solution was concentrated and recrystallized to give 9.8 g ofcolorless solid. Enantiomeric excess of this solid was determined bychiral HPLC on a Chiralpak AD column using 5% ethanol/hexane as theeluent. It showed to have 96% e.e with the first eluting peak as themajor product.

[0695] Step 10: Demethylation of5-(4′-methoxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide(4R,5R)

[0696] To a solution of 47 g (99 mmol) of enantiomeric-enriched(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Step9) in 500 mL of methylene chloride at −10° C. was added dropwise asolution of boron tribromide (297 mL, 1M in methylene chloride, 297mmol), and the resulting solution was stirred cold (−5° C. to 0° C.) for1 hour or until the reaction was complete. The reaction was cooled in anacetone-dry ice bath at −10° C., and slowly quenched with 300 mL ofwater. The mixture was warmed to 10° C., and further diluted with 300 mLof saturated sodium bicarbonate solution to neutralize the mixture. Theaqueous layer was separated and extracted with 300 mL of methylenechloride, and the combined extracts were washed with 200 mL of water,brine, dried over MgSO₄ and concentrated in vacuo. The residue wasdissolved in 500 mL of ethyl acetate and stirred with 50 mL of glacialacetic acid for 30 minutes at ambient temperature. The mixture waswashed twice with 200 mL of water, 200 mL of brine, dried over MgSO₄ andconcentrated in vacuo to give the crude 4-hydroxyphenyl intermediate.The solid residue was recrystallized from methylene chloride to give37.5 g (82%) of the desired5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxideas a white solid: ¹H NMR (CDCl₃) δ 0.84-0.97 (m, 6H), 1.1-1.5 (m, 10H),1.57-1.72 (m, 1H), 2.14-2.28 (m, 1H), 2.83 (s, 6H), 3.00 (d, J=15.3 Hz,1H), 3.16 (d, J=15.3 Hz, 1H), 4.11 (s, 2H), 5.48 (s, 1H), 6.02 (d, J=2.4Hz, 1H), 6.55 (dd, J=9, 2.4 Hz, 1H), 6.88 (d, 8,7 Hz, 2H), 7.38 (d,J=8.7 Hz, 2H), 7.91 (d, J=9 Hz, 2H).

[0697] Alternatively, enantiomeric-enriched5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide,the intermediate just described, can be prepared vianon-enantioselective synthesis followed by chiral chromatographyseparation. Oxidation of aryl-3-hydroxypropylsulfide (obtained from Step4) with m-chloroperbenzoic acid (under the similar conditions as in Step8, but with 2.2 equivalent of m-CPBA) gave the racemic sulfoneintermediate. The sulfone was carried through the synthetic sequences(under the same conditions as in Step 7 and Step 9) to give the racemic5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide.The two enantiomers were further separated into the desiredenantiomeric-enriched5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxideby appropriate chiral chromatographic purification.

[0698] Step 11: Preparation of ester intermediate

[0699] To a solution of 1.0 g (2.18 mmol) of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzo-thiepine-1,1-dioxide(obtained from Step 10) in 10 mL dimethylformamide was added 60 mg (2.38mmol) of 95% sodium hydride and stirred for 15 minutes. To the reactionmixture was added 400 pL (2.52 mmol) of benzyl 2-bromoacetate andstirred for two hours. Water was added to the reaction mixture,extracted with ethyl acetate, washed with brine, dried over magnesiumsulfate, filtered and the solvent evaporated to afford 1.30 g (98%) ofthe ester intermediate: ¹H NMR (CDCl₃) δ 0.88-0.94 (m, 6H), 1.13-1.46(m, 10H), 1.60-1.64 (m, 1H), 2.20-2.24 (m, 1H), 2.81 (s, 6H), 3.00 (d,J=15.1 Hz, 1H), 3.16 (t, J=15.1 Hz, 1H), 4.11 (s, 1H), 5.26 (s, 2H),5.49 (s, 1H), 6.04 (d, J=2.4 Hz, 1H), 6.63 (dd, J=8.9, 2.4 Hz, 1H), 6.95(d, J=8.7 Hz, 2H), 7.37 (s, 5H), 7.42 (d, J=8.5 Hz, 2H), 7.93 (d, J=8.9Hz, 1H).

[0700] Step 12: Preparation of acid

[0701] A solution of 1.30 g (2.14 mmol) of ester intermediate (obtainedfrom Step 1) in 40 mL ethanol with 10% palladium on carbon was placedunder an atmosphere of hydrogen gas (40 psi) for three hours. Thereaction mixture was filtered through celite and the solvent wasevaporated to afford the desired title compound as a white solid: mp119 - 123° C.; ¹H NMR (CDCl₃) δ 0.89-0.94 (m, 6H), 1.19-1.43 (m, lOH),1.61-1.65 (m, 1H), 2.17-2.21 (m, 1H), 2.85 (s, 6H), 3.02 (d, J=15.1 Hz,1H), 3.17 (t, J=14.9 Hz, 1H), 4.12 (s, 1H), 4.72 (s, 2H), 5.51 (s, 1H),6.17 (s, 1H), 6.74 (d, J=9.1 Hz, 1H), 6.99 (d, J=8.3 Hz, 2H), 7.46 (d,J=8.5 Hz, 2H), 7.97 (d, J=8.7 Hz, 1H). HRMS. Calc'd for C₂₈H₄₀NO₆S:518.2576. Found: 518.2599.

EXAMPLE 1403

[0702]

[0703](4R-cis)-N-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxyacetyl]glycine

[0704] Step 1: Preparation of glycine ester intermediate

[0705] To a solution of 6.4 g (13.9 mmol) of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzo-thiepine-1,1-dioxide(obtained from Example 1402, Step 10) and 2.9 g (21.0 mmol) of potassiumcarbonate in 100 ml of acetone was added 3.8 g (21.0 mmol) ofN-(chloroacetyl)glycine ethyl ester and 50 mg (0.14 mmol) oftetrabutylammonium iodide. The reaction was heated to reflux for 2 days,cooled to ambient temperature and stirred for 20 hours, then partitionedbetween ethyl acetate and water. The organic layer was washed withbrine, dried over MgSO₄, and concentrated in vacuo. Purification bysilica gel chromatography (Waters Prep-500) using 50% ethylacetate/hexanes afforded 7.5 g (90%) of glycine ester intermediate as awhite foam: ¹H NMR (CDCl₃) δ 0.86-0.98 (m, 6H), 1.04-1.56 (m, 13H),1.58-1.71 (m, 1H), 2.14-2.29 (m, 1H), 2.73 (s, 6H), 3.08 (ABqf JM =15.3Hz, J=48.9 Hz, 2H), 4.06-4.19 (m, 6H), 4.25 (q, J=7.0 Hz, 2H), 4.57 (s,2H), 5.50 (s, 1H), 5.98 (s, 1H), 6.56 (d, J=8.6 Hz, 1H), 6.98 (d, J=8.5Hz, 2H), 7.17 (s, 1H), 7.47 (d, J=8.3 Hz, 2H), 7.91 (d, J=8.7 Hz, 1H)

[0706] Step 2: Preparation of acid

[0707] A solution of 7.3 g (12.1 mmol) of glycine ester intermediate(obtained from Step 1) and 1.5 g LiOH.H₂O (36.3 mmol) in 60 mL of THFand 60 mL of water was heated to 45° C. for 2 hours. This was thencooled to ambient temperature, acidified with 1 N HCl and partitionedbetween ethyl acetate and water. The organic layer was washed withbrine, dried over MgSO₄, and concentrated in vacuo. Purification byrecrystallization from ethyl acetate gave 5.45 g (78%) of the desiredtitle compound as a white crystalline solid: mp 149-150° C.; ¹NMR(CD₃OD) δ 0.88-0.98 (m, 6H), 1.06-1.56 (m, 10H), 1.70-1.84 (m, 1H),2.06-2.20 (m, 1H), 2.79 (s, 6H), 3.11 (AB_(q), J_(Ab)=15.3 Hz, J=21.6Hz, 2H), 4.01 (s, 2H), 4.07 (s, 1H), 4.61 (s, 2H), 5.31 (s, 1H), 6.04(s, IH), 6.57 (d, J=9.0 Hz, 1H), 7.08 (d, J=7.8 Hz, 2H), 7.44 (d, J=8.1Hz, 2H), 7.76 (d, J=9.0 Hz, 1H), 8.42 (m, 1H). HRMS(ES+) Calc'd forC₃₀H₄₂N₂O₇S: 575.2712. Found: 575.2790. Anal. Calc'd for: C₃₀H₄₂N₂O₇S C,62.69; H, 7.37; N, 4.87. Found: C, 62.87; H, 7.56; N, 4.87.

EXAMPLE 1403

[0708]

[0709](4R-cis)-N-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxyacetyllglycine

[0710] Step 1: Preparation of glycine ester intermediate

[0711] To a solution of 6.4 g (13.9 mmol) of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzo-thiepine-1,1-dioxide(obtained from Example 1402, Step 10) and 2.9 g (21.0 mmol) of potassiumcarbonate in 100 ml of acetone was added 3.8 g (21.0 mmol) ofN-(chloroacetyl)glycine ethyl ester and 50 mg (0.14 mmol) oftetrabutylammonium iodide. The reaction was heated to reflux for 2 days,cooled to ambient temperature and stirred for 20 hours, then partitionedbetween ethyl acetate and water. The organic layer was washed withbrine, dried over MgSO₄, and concentrated in vacuo. Purification bysilica gel chromatography (Waters Prep-500) using 50% ethylacetate/hexanes afforded 7.5 g =* (90%) of glycine ester intermediate asa white foam: ¹H NMR (CDCl₃) δ 0.86-0.98 (m, 6H), 1.04-1.56 (m, 13H),1.S8-1.71 (m, 1H), 2.14-2.29 (m, 1H), 2.73 (s, 6H), 3.08 (ABq, J=15.3Hz, J=48.9 Hz, 2H), 4.06-4.19 (m, 6H), 4.25 (q, J=7.0 Hz, 2H), 4.57 (s,2H), 5.50 (s, 1H), 5.98 (s, 1H), 6.56 (d, J=8.6 Hz, 1H), 6.98 (d, J=8.5Hz, 2H), 7.17 (s, 1H), 7.47 (d, J=8.3 Hz, 2H), 7.91 (d, J=8.7 Hz, 1H).

[0712] Step 2: Preparation of acid

[0713] A solution of 7.3 g (12.1 mmol) of glycine ester intermediate(obtained from Step 1) and 1.5 g LiOH.H₂O (36.3 mmol) in 60 mL of THFand 60 mL of water was heated to 45° C. for 2 hours. This was thencooled to ambient temperature, acidified with 1 N HCl and partitionedbetween ethyl acetate and water. The organic layer was washed withbrine, dried over MgSO₄, and concentrated in vacuo. Purification byrecrystallization from ethyl acetate gave 5.45 g (78%) of the desiredtitle compound as a white crystalline solid: mp 149-150° C.; ¹H NMR(CD₃OD) δ 0.88-0.98 (m, 6H), 1.06-1.56 (m, 10H), 1.70-1.84 (m, 1H),2.06-2.20 (m, 1H), 2.79 (s, 6H), 3.11 (ABqI JA =15.3 Hz, J=21.6 Hz, 2H),4.01 (s, 2H), 4.07 (s, 1H), 4.61 (s, 2H), 5.31 (s, 1H), 6.04 (s, 1H),6.57 (d, J=9.0 Hz, 1H), 7.08 (d, J=7.8 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H),7.76 (d, J=9.0 Hz, 1H), 8.42 (m, 1H). HRMS(ES+) Calc'd for C₃₀H₄₂N₂O₇S:575.2712. Found: 575.2790. Anal. Calc'd for: C₃₀H₄₂N₂O₇S C, 62.69; H,7.37; N, 4.87. Found: C, 62.87; H, 7.56; N, 4.87.

EXAMPLE 1404

[0714]

[0715](4R-cis)-5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentanoicacid

[0716] Step 1: Preparation of ester intermediate

[0717] A solution of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide(1.0 g, 2.2 mmol, obtained from Example 1402, Step 10) in acetone (10mL) at 25° C. under N₂ was treated with powdered K₂CO₃ (0.45 g, 3.3mmol, 1.5 eq.), benzyl 5-bromovalerate (0.88 g, 3.3 mmol, 1.5 eq.) and acatalytic amount of tetra-n-butylammonium iodide (2 mg), and theresulting solution was stirred at 65° C. for 24 hours. The pale amberslurry was cooled to 25° C. and was concentrated in vacuo to provide ayellow residue. Purification by flash chromatography (2.4×30 cm silica,20-40% EtOAc/hexane) afforded the ester intermediate (1.2 g, 86%) as acolorless oil: ¹NMR (CDCl₃) δ 0.91 (m, 6H), 1.11-1.47 (br m, 10H), 1.64(m, 1H), 1.86 (m, 2H), 2.21 (m, 1H), 2.47 (m, 2H), 2.81 (s, 6H), 3.05(ABq, J=15.1 Hz, J=47.7 Hz, 2H), 4.10 (d, J=7.9 Hz, 1H), 5.13 (s, 2H),5.47 (s, 1H), 6.00 (d, J=2.5 Hz, 1H), 6.50 (dd, J=8.9, 2.5 Hz, 1H), 6.91(d, J=8.7 Hz, 2H), 7.36 (m, 5H), 7.40 (d, J=8.5 Hz, 2H), 7.86 (d, J=8.9Hz, 1H); HRMS. Calc'd for C₃₈H₅₁NO₆S: 650.3515. Found: 650.3473.

[0718] Step 2: Preparation of acid

[0719] A solution of the ester intermediate (0.99 g, 1.5 mmol, obtainedfrom Step 1) in ethanol (7.5 mL) at 25° C. was treated with 5% palladiumon carbon (0.15 g, 10 wt %) then stirred under an atmosphere (1 atm) ofH₂ via hydrogen balloon. Every 10 min, hydrogen gas was bubbled throughthe slurry for 1 min, for a total reaction time of 4 hours. The slurrywas placed under an atmosphere of N₂ and nitrogen was bubbled throughthe reaction mixture for 10 min. The mixture was filtered through a plugof Celiteo (10 g) and concentrated in vacuo to give a white foam.Purification by flash chromatography (2.6×25 cm silica, 1.5%EtOH/CH₂Cl₂) afforded the desired title compound (0.54 g, 63%) as awhite foam: mp: 76-79° C.; ¹NMR (CDCl₃) δ 0.90 (m, 6H), 1.10-1.46 (br m,10H), 1.62 (m, 1H), 1.87 (m, 4H), 2.20 (m, 1H), 2.45 (m, 2H), 2.81 (s,6H), 3.05 (ABq, J=15.1 Hz, J=49.7 Hz, 2H), 4.00 (s, 2H), 4.09 (s, 1H),5.45 (s, 1H), 5.99 (d, J=2.4 Hz, 1H), 6.48 (dd, J=8.9, 2.4 Hz, 1H), 6.91(d, J=8.7 Hz, 2H), 7.39 (m, 5H), 7.39 (d, J=8.3 Hz, 2H), 7.84 (d, J=8.9Hz, 1H); HRMS. Calc'd for C₃₁H₄₅NO₆S: 560.3046. Found: 560.3043.

EXAMPLE 1405

[0720]

[0721] (4R-cis)-4-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy-1-butanesulfonamide

[0722] Step 1: Preparation of sulfonic acid intermediate

[0723] A solution of 7.4 g (16.1 mmol) of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzo-thiepine-1,1-dioxide(obtained from Example 1402, Step 10) in acetone (35 mL) at 25° C. underN₂ was treated with powdered potassium carbonate (3.3 g, 24.1 mmol, 1.5equiv.) and 1,4-butane sultone (2.5 mL, 24.1 mmol, 1.5 equiv.) andstirred and heated at 65° C. for 64 h. The solution was allowed to coolto 25° C. and quenched by the addition of water (50 mL), until ahomogeneous mixture was obtained. The clear and colorless solution wasadded dropwise to a 4 N HCl solution cooled to 0° C. over a 30 minperiod. The mixture was vigorously stirred for 4 h then allowed to warmto ambient temperature and stirred for an additional 16 h. The resultantwhite precipitate was filtered and washed with water and dried in vacuoto provide 8.8 g (92%) of the desired sulfonic acid as a white solid. Aportion of the white solid was recrystallized from CH₃CN/hexane to givethe desired sulfonic acid as colorless needles: mp 229-236° C.(decomposed); ¹NMR (DMSO-d₆) δ 0.82 (m, 6H), 1.02-1.33 (br m, 10H), 1.59(m, 1H), 1.73 (m, 4H), 2.00 (s, 1H), 2.48 (m, 2H), 2.71 (s, 6H), 2.98(s, 1H), 3.86 (s, 1H), 3.93 (m, 2H), 5.08 (s, 1H), 5.89 (s, 1H), 6.52(dd, J=8.9, 2.4 Hz, 1H), 6.92 (d, J=8.3 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H),7.60 (d, J=8.9 Hz, 1H); Anal. Calc'd for C₃₀H₄₅NO₇S₂: C, 60.48; H, 7.61;N, 2.35. Found: C, 60.53; H, 7.70; N, 2.42.

[0724] Step 2: Preparation of7-(dimethylamino)-benzothiepin-5-yl]phenoxy-1-butanesulfonamide To asolution of 1.12 g (1.88 mmol) of the sulfonic acid (obtained fromStep 1) in 10 mL CH₂Cl₂ was added 785 mg (3.77 mmol) PCl₅ and stirredfor 1 hour. Water was added and the mixture was extracted and washedwith brine. Dried with MgSO₄, filtered and solvent evaporated. To theresidue was added 30 mL of 0.5M NH₃ in dioxane and stirred 16 hours. Theprecipitate was filtered and the solvent evaporated. The residue waspurified by MPLC (33% EtOAc in hexane) to afford the desired titlecompound as a beige solid (125 mg, 11%): mp 108-110° C.; ¹NMR (CDCl₃) δ0.85-0.93 (m, 6H), 1.13-1.59 (m, 10H), 1.60-1.67 (m, 1H), 1.94-2.20 (m,5H), 2.82 (s, 6H), 2.99 (d, J=15.3 Hz, 1H), 3.15 (t, J=15.3 Hz, 1H),3.23 (t, J=7.7 Hz, 2H), 4.03 (t, J=5.8 Hz, 2H), 4.08-4.10 (m, 1H), 4.79(s, 2H), 5.47 (s, 1H), 6.02 (d, J=2.4 Hz, 1H), 6.52 (dd, J=8.9, 2.6 Hz,1H), 6.91 (d, J=8.9 Hz, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.89 (d, J=8.9 Hz,1H). HRMS.

[0725] Calc'd for C₃₀H₄₇N₂O₆S₂: 595.2876. Found: 595.2874.

EXAMPLE 1406

[0726]

[0727] (4R-cis) -1-[3-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl] phenoxy) propyl]-4-aza-1-azoniabicyclo[2.2.2]octane, methanesulfonate (salt)

[0728] Step 1: Preparation of dimesylate intermediate

[0729] To a cooled (−20° C.) solution of 5.0 g (65.7 mmol) of1,3-propanediol in 50 mL of triethylamine and 200 mL of methylenechloride was added 15.8 g (137.9 mol) of 20 methanesulfonyl chloride.The mixture was stirred for 30 minutes, then warmed to ambienttemperature and partitioned between ethyl acetate and 1N HCl. Theorganic layer was washed with brine, dried over MgSO₄₁ and concentratedin vacuo to give 13.5 g (89%) of dimesylate intermediate as a clearyellowish oil: ¹H NMR (CDCl₃) δ 2.12 (quintet, J=4.5 Hz, 4H), 3.58 (s,6H) , 4.38 (t, J=5.4 Hz)

[0730] Step 2: Preparation of propyl mesylate intermediate

[0731] To a solution of 2.4 g (5.2 mmol) of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenz-othiepine-1,1-dioxide(obtained from Example 1402, Step 10) and 6.0 g (26.1 mmol) ofdimesylate intermediate (obtained from Step 1) in 50 mL of acetone wasadded 3.6 g (26.1 mmol) of K₂CO₃. The reaction was heated to refluxovernight then cooled to ambient temperature and concentrated in vacuo.The residue was partitioned between ethyl acetate and water. The organiclayer was washed with brine, dried over MgSO₄, and concentrated invacuo. Purification by silica gel chromatography (Waters-Prep 500) using36% ethyl acetate/hexanes afforded 2.8 g (90%) of the propyl mesylateintermediate as a white foam: ¹H NMR (CDCl₃) δ 0.86-0.95 (m, 6H),1.06-1.52 (m, 10H), 1.57-1.70 (m, 1H), 2.14-2.32 (m, 3H), 2.84 (s, 6H),3.02 (s, 3H), 3.08 (ABq, JA =15.0 Hz, J=46.9 Hz, 4.09-4.18 (m, 3H), 4.48(t, J=6.0 Hz, 2H), 5.49 (s, 1H), 6.11 (s, 1H), 6.65 (d, J=8.7 Hz, 1H),6.94(d, J=8.6 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.94 (d, J=8.9 Hz, 1H).

[0732] Step 3: Preparation of quaternary salt

[0733] To a solution of 1.2 g (2.0 mmol) of propyl mesylate intermediate(obtained from Step 2) in 20 ml of acetonitrile was added 0.3 g (2.9mmol) of 1,4-diazabicyclo[2.2.2]octane (DABCO). The reaction mixture wasstirred at 60° C. for three hours, then cooled to ambient temperatureand concentrated in vacuo. Purification by trituration with methylenechloride/ethyl ether gave 1.3 g (91%) of the desired title compound as awhite solid: mp. (dec) 230-235° C.; ¹NMR (CDCl₃) δ 0.86-0.95 (m, 6H),1.04-1.52 (m, 10H), 1.57-1.70 (m, 1H), 2.12-2.25 (m, 3H), 2.28-2.39 (m,2H), 2.83 (s, 6H), 3.04 (s, 3H), 3.09 (AB_(q), J_(AB)=15-6 Hz, J=42.2Hz, 2H) 3.22-3.32 (m, 6H), 3.56-3.66 (m, 6H), 3.73-3.83 (m, 2H),4.06-4.17 9m, 3H), 5.47 (s, 1H), 5.97 (s, 1H), 6.51 (d, J=8.6 Hz, 1H),6.90(d, J=8.6 Hz, 2H), 7.41 (d, J=8.7 Hz, 2H), 7.89 (d, J=8.9 Hz, 1H).MS (ES+) m/e 612.4. HRMS (ES+) Calc'd for C₃H₅₄N₃O₄S⁺: 612.3835. Found:612.3840.

EXAMPLE 1407

[0734]

[0735](4R-cis)-1-[3-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yllphenoxy]propyl]-4-aza-1-azoniabicyclo[2.2.2]octane,4-methylbenzenesulfonate(salt)

[0736] Step 1: Preparation of propyl tosylate intermediate A solution of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide(5.0 g, 10.9 mmol, obtained from Example 1402, Step 10) in acetone (100mL) at 25° C. under N₂ was treated with powdered K₂CO₃ (3.8 g, 27.2mmol, 2.5 eq.) and 1,3-propanediol di-p-tosylate (13.0 g, 32.6 mmol, 3.0eq.), and the resulting mixture was stirred at 65° C. for 21 hours. Thecream-colored slurry was cooled to 25° C. and was filtered through asintered glass funnel. The filtrate was concentrated and the residue wasdissolved in EtOAc (150 mL). The organic layer was washed with saturatedaqueous NaHCO₃(2×150 mL) and saturated aqueous NaCl (2×150 mL), and wasdried (MgSO₄) and concentrated in vacuo to provide a pale orange oil.Purification by flash chromatography (4.4×35 cm silica, 20-30%EtOAc/hexane) afforded the propyl tosylate intermediate (6.0 g, 80%) asa white foam: ¹H NMR (CDCl₃) δ 0.91 (m, 6H), 1.11-1.47 (br m, 10H), 1.63(m, 1H), 2.14 (m, 2H), 2.21 (m, 1H), 2.41 (s, 3H), 2.81 (s, 6H), 3.06(ABq, J=15.1 Hz, J=49.0 Hz, 2H), 4.01 (t, J=5.3 Hz, 2H), 4.10 (m, IH),4.26 (t, J=5.9 Hz, 2H), 5.29 (s, 1H), 5.48 (s, 1H), 5.98 (s, 1H), 6.51(dd, J=8.9, 1.8 Hz, 1H), 6.83 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H),7.39 (d, J 8.3 Hz, 2H), 7.78 (d, J=8.3 Hz, 2H), 7.88 (d, J=8.9 Hz, 1H).

[0737] Step 2: Preparation of quaternary salt

[0738] A solution of the propyl tosylate intermediate (1.05 g, 1.56mmol, obtained from Step 1) in acetonitrile (15 mL) at 25° C. under N₂was treated with diazabicyclo[2.2.2]octane (DABCO, 0.26 g, 2.34 mmol,1.5 eq.) and stirred at 50° C. for 6 hours, then at 25° C. for 14 hours.The pale amber solution was cooled to 25° C. and concentrated in vacuoto provide an amber oil. The residue was dissolved in a minimal amountof CH₂Cl₂ (5 mL) and diluted with Et₂O (100 mL) while vigorouslystirring for 4 hours, during which time a white solid precipitated. Thewhite solid was collected (Et₂O wash) to give the desired title compound(1.11 g, 90%) as a white amorphous solid: mp 136.5-142° C. (decomposed);¹NMR (CDCl₃) δ 0.89 (m, 6H), 1.12-1.43 (br m, 9H), 1.61 (m, 1H), 1.65(m, 1H), 2.18 (m, 1H), 2.22 (m, 2H), 2.27 (s, 3H), 2.78 (s, 6H), 3.07(ABq, J=15.1 Hz, J=39.5 Hz, 2H), 3.49 (br s, 6H), 3.68 (m, 1H), 3.74 (brs, 6H), 3.96 (br s, 2H), 4.09 (d, J=7.3 Hz, 1H), 5.46 (s, 1H), 5.96 (d,J=2.4 Hz, 1H), 6.49 (dd, J=8.9, 2.4 Hz, 1H), 6.83 (d, J=8.5 Hz, 2H),7.11 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 7.74 (d, J=8.1 Hz, 2H),7.87 (d, J=8.9 Hz, 1H); HRMS. Calc'd for C₃,H₅₄N30₄S: 612.3835. Found:612.3832.

EXAMPLE 1408

[0739]

[0740] (4R-cis)-1-[4-[4-[3, 3-Dibutyl-7-(diethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yllphenoxy]butyl]-4-aza-1-azoniabicyclo[2.2.2] octanemethanesulfonate (salt)

[0741] Step 1: Preparation of butyl mesylate intermediate

[0742] A mixture of 1.00 g (2.18 mmol) of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzo-thiepine-1,1-dioxide(obtained from Example 1402, Step 10), 2.68 g (10.88 mmol) of busulfan,and 1.50 g (10.88 mmol) of potassium carbonate in 20 mL of acetone wasstirred at reflux overnight. The mixture was concentrated in vacuo andthe crude was dissolved in 30 mL of ethyl acetate. The insoluble solidwas filtered off andthe filtrate was concentrated in vacuo. Theresulting white foam was chromatographed through silica gel column, andeluted with 30% ethyl acetate/hexane to give 1.02 g (77%) of butylmesylate intermediate as a white solid: ¹NMR (CDCl₃) δ 0.90 (m, 6H),1.20-1.67 (m, 12H), 1.98 (m, 4H), 2.22 (m, 1H), 2.83 (s, 6H), 3.04 (s,3H), 3.08 (ABq, 2H), 4.05 (t, J=5.55 Hz, 2H), 4.11 (d, J=6.90 Hz, 1H),4.35 (t, J=6.0 Hz, 2H), 5.49 (s, 1H), 6.00 (d, J=2.4 Hz, 1H), 6.52 (dd,J=9.0 Hz, 2.7 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H),7.90 (d, J=9.0 Hz, 1H).

[0743] Step 2: Preparation of ester intermediate

[0744] A solution of 520 mg (0.85 mmol) of butyl mesylate intermediate(obtained from Step 1) and 191 mg (1.71 mmol) of DABCO in 10 mL ofacetonitrile was stirred at 80° C. for 4 hours. The reaction mixture wasconcentrated in vacuo to yield a white foam. The foam was crushed andwashed with ether. The solid was filtered off and dried in vacuo to give540 mg (88%) of the desired title compound which was recrystallized frommethylene chloride and acetone as a white solid: mp 248-251° C.; ¹NMR(CDCl₃) δ 0.91 (m, 6H), 1.14-1.47 (m, 14H), 1.63 (m, 1H), 1.96 (m, 4H),2.21 (m, 1H), 2.77 (s, 3H), 2.82 (s, 3H), 3.07 (ABq, 2H), 3.26 (t, J=7.1Hz, 6H), 3.60 (m, 8H), 4.08 (m, 3H), 5.47 (s, 1H), 5.99 (d, J=2.4 Hz,1H), 6.51 (dd, J=8.9 Hz, 2.6 Hz, 1H), 6.91 (d, J=8.7 Hz, 2H), 7.41 (d,J=8.1 Hz, 2H), 7.89 (d, J=9.0 Hz, 1H).

EXAMPLE 1409

[0745]

[0746](4R-cis)-1-[4-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]-4-aza-1-azoniabicyclo[2.2.2]octane-4-methylbenzenesulfonate(salt)

[0747] Step 1: Preparation of propyl tosylate intermediate

[0748] A solution of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide(5.0 g, 10.9 mmol, obtained from Example 1402, Step 10) in acetone (100mL) at 25° C. under N₂ was treated with powdered K₂CO₃ (3.8 g, 27. 2mmol, 2. 5 eq.) and 1,4-butanediol di-p-tosylate (13.0 g, 32.6 mmol, 3.0eq.), and the resulting solution was stirred at 65° C. for 21 hours. Thecream-colored slurry was cooled to 25° C. and filtered through asintered glass funnel. The filtrate was concentrated and the residue wasdissolved in EtOAc (150 mL). The organic layer was washed with saturatedaqueous NaHCO₃ (2×150 mL) and saturated aqueous NaCl (2×150 mL). Theextract was dried (MgSO₄) and concentrated in vacuo to provide a paleorange oil. Purification by flash chromatography (4.4×35 cm silica,20-30% EtOAc/hexane) afforded the propyl tosylate intermediate (6.0 g,80%) as a white foam: ¹NMR (CDCl₃) 67 0. 89 (m, 6H), 1.10-1.44 (br m,10H), 1.61 (m, 1H), 1.84 (m, 4H), 2.19 (m, 1H), 2.43 (s, 3H), 2.80 (s,6H), 3.03 (ABq, J=15.1 Hz, J=46.3 Hz, 2H), 3.93 (m, 2H), 4.06-4.13 (m,4H), 5.44 (s, 1H), 5.96 (s, 1H), 6.46 (dd, J=8.9, 1.4 Hz, 1H), 6.85 (d,J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 7.78 (d,J=8.9 Hz, 2H), 7.83 (m, 1H).

[0749] Step 2: Preparation of quaternary salt

[0750] A solution of propyl tosylate intermediate (5.8 g, 8.5 mmol,obtained from Step 1) in acetonitrile (100 mL) at 25° C. under N₂ wastreated with diazabicyclo[2.2.2]octane (DABCO, 1.1 g, 10.1 mmol, 1.2eq.) and stirred at 45° C. for 6 hours. The pale yellow solution wascooled to 25° C. and concentrated in vacuo to provide an off-whitesolid. The residue was dissolved in a minimal amount of CH₂Cl₂ (5 mL)and diluted with Et₂O (100 mL) while vigorously stirring for 3 hours,during which time a white solid precipitated. The white solid wascollected and recrystallized from EtOAc/hexane to give the desired titlecompound (5.7 g, 85%) as colorless needles: mp 223-231° C. (decomposed);¹H NMR (CDCl₃) δ 0.86 (m, 6H), 1.09-1.43 (br m, 12H), 1.61-1.90 (br m,SH), 2.13 (m, 1H), 2.25 (s, 3H), 2.75 (s, 6H), 3.03 (ABq, J=15.1 Hz,J=30.0 Hz, 2H), 3.05 (br s, 6H), 3.37 (br s, 6H), 3.89 (m, 2H), 4.07 (d,J=7.5 Hz, 1H), 5.39 (s, 2H), 5.97 (d, J=1.6 Hz, 1H), 6.44 (dd, J=8.9,2.0 Hz, 1H), 6.87 (d, J=8.3 Hz, 2H), 7.08 (d, J=8.1 Hz, 2H), 7.37 (d,J=8.3 Hz, 2H), 7.71 (d, J=8.1 Hz, 2H), 7.80 (d, J=8.9 Hz, 1H); HRMS.Calc'd for C₃₆H₅₆N₃O₄S: 626.3992. Found: 626.3994. Anal. Calc'd forC₄₃H₆₃N₃O₇S₂: C, 64.71; H, 7.96; N, 5.27. Found: C, 64.36; H, 8.10; N,5.32.

EXAMPLE 1410

[0751]

[0752](4R-cis)-4-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]-N,N,N-triethyl-1-butanaminium

[0753] A solution of 1 g (1.64 mmol) of the butyl mesylate intermediate(obtained from Example 1408, Step 1) and 15 mL of triethylamine in 10 mLof acetonitrile was heated at 50° C. for 2 days. The solvent wasevaporated and the residue was triturated with ether and ethyl acetateto afford 500 mg (43%) of product as a semi-solid. ¹NMR (CDCl₃) δ 0.8(m, 6 H), 1-1.6 (m, 24 H), 2.1 (m, 1 H), 2.6 (s, 3 H), 2.7 (s, 6 H), 2.9(d, J=15 Hz, 1 H), 3.0 (d, J=15 Hz, 1 H), 3.3 (m, 8 H), 4.0 (m, 4 H),5.3 (s, 1 H), 5.9 (s, 1 H), 6.4 (m, 1 H), 6.8 (d, J=9 Hz, 2 H), 7.4 (d,J=9 Hz, 2 H), 7.8 (d, J=7 Hz, 1 H). MS m/e 615.

EXAMPLE 1411

[0754]

[0755](4R-cis)-1-[4-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,l-dioxido-1-benzothiepin-5-yllphenoxylbutyl]-3-hydroxypyridinium,methanesulfonate (salt)

[0756] A solution of 1 g (1.64 mmol) of the butyl mesylate intermediate(obtained from Example 1408, Step 1) and 234 mg (2.46 mmol) of 3-hydroxypyridine in 1 mL of dimethylformamide was heated at 70° C. for 20 hours.

[0757] The solvent was evaporated and the residue was triturated withether and ethyl acetate to afford 990 mg (86%) of product as asemi-solid: ¹NMR (CDCl₃) δ 0.9 (m, 6 H), 1-1.5 (m, 10 H), 1.7 (m, 1 H),1.9 (m, 2 H), 2-2.4 (m, 3 H), 2.9 (s, 6 H), 3.1 (d, J=15 Hz, 1 H), 3.2(d, J=15 Hz, 1 H), 4.1 (m, 3 H), 4.7 (m, 2 H), 5.5 (s, 1 H), 6.1 (s, 1H), 6.6 (m, 1 H), 6.9 (d, J=9 Hz, 2 H), 7.4 (d, J=9 Hz, 2 H), 7.7 (m, 1H), 8.0 (m, 2 H), 8.2 (m, 1 H), 9.1 (s, 1 H). MS m/e 609.

EXAMPLE 1412

[0758]

[0759](4R-cis)-1-[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyl]quinolinium,methanesulfonate (salt)

[0760] Step 1: Preparation of pentyl mesylate intermediate

[0761] To a stirred solution of 231 mg (5.79 mmol, 60% disp.) of NaH in22 mL of DMF was added 2.05 g (4.45 mmol) of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetra-hydrobenzothiepine-1,1-dioxide(obtained from Example 1402, Step 10), and the resulting solution wasstirred at ambient temperature for 1 hour. To the mixture was added18.02 g (55.63 mmol) of 1,5-diiodopentane and the solution was stirredovernight at ambient temperature. DMF was removed by high vacuum and theresidue was extracted with ethyl acetate and washed with brine. Theextract was dried over MgSO₄, and the concentrated residue was purifiedby column chromatography to give the pentyl mesylate intermediate: ¹NMR(CDCl₃) δ 0.90(q, 6H), 1.05-2.0 (m, 17H), 2.2 (t, 1H), 2.8 (s, 6h), 3.0(q, 2H), 3.22 (t, 2H), 3.95 (t, 2H), 4.1 (s, 1H), 5.42 (s, 1H), 6.1 (d,1H), 6.6 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).

[0762] Step 2: Preparation of quaternary salt

[0763] To 1.0 g (1.53 mmol) of the pentyl mesylate intermediate(obtained from Step 1) was added 3.94 g (30.5 mmol) of quinoline and 30mL of acetonitrile.

[0764] The solution was heated at 45° C. under N₂ for 10 days.

[0765] The concentrated residue was purified by reverse phase C18 columnchromatography. The obtained material was exchanged to its mesylateanion by ion exchange chromatography to give the desired title compoundas a solid: mp 136° C.; ¹H NMR (CDCl₃) δ 0.95(q, 6H), 1.05-2.25 (m,18H), 2.8 (s, 9H), 3.0 (q, 2H), 3.95 (t, 2H), 4.1 (s, 1H), 5.28 (t, 2H),5.42 (s, 1H), 5.95 (s, 1H), 6.45 (d, 1H), 6.82 (d, 2H), 7.4 (d, 2H),7.82 (d, 1H), 7.9 (t, 1H), 8.2 (t, 2H), 8.3 (q, 2H), 8.98 (d, 1H), 10.2(d, 1H). HRMS. Calc'd for C₄₀H₅₃N₂0₄S: 657.3726. Found: 657.3736. Anal.Calc'd for C₄₀H₅₃N₂O₄S.CH₃0₃S: C, 65.40; H, 7.50; N, 3.72; S, 8.52.Found: C, 62.9; H, 7.42; N, 3.56; S, 8.41.

EXAMPLE 1413

[0766]

[0767](4S-cis)-[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyllpropanedioicacid

[0768] Step 1: Preparation of pentyl bromide intermediate

[0769] To a stirred solution of 0.63 g (15.72 mmol, 60% disp) of NaH in85 mL of DMF was added 6.0 g (13.1 mmol) of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetra-hydrobenzothiepine-1,1-dioxide(obtained from Example 1402, Step 10), and the resulting solution wasstirred at ambient temperature for 1 hour. To the solution was added37.7 g (163.75 mmol) of 1,5-dibromopentane, and the mixture was stirredovernight at ambient temperature. DMF was removed in vacuo and theresidue was extracted with ethyl acetate and washed with brine. Theextract was dried over MgSO₄, and the concentrated residue was purifiedby column chromatography to give the pentyl bromide intermediate: ¹NMR(CDCl₃) δ 0.90 (q, 6H), 1.05-2.0 (m, 17H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0(q, 2H), 3.4 (t, 2H), 3.95 (t, 2H), 4.1 (s, 1H), 5.42 (s, 1H), 6.0 (s,1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).

[0770] Step 2: Preparation of dibenzyl ester intermediate

[0771] To the mixture of 59 mg (1.476 mmol, 60% disp) of NaH in 27 mL ofTHF and 9 mL of DMF at 0° C. was added 0.84 g (2.952 mmol) of dibenzylmalonate (Aldrich), and the resulting solution was stirred at ambienttemperature for 15 min. To the solution was added 0.5987 g (0.984 mmol)of the pentyl bromide intermediate, and the mixture was stirred at 80°C. overnight. Solvent was removed in vacuo, and the residue wasextracted with methylene chloride and washed with brine. The extract wasdried over MgSO₄, and the concentrated residue was purified by columnchromatography to give the dibenzyl ester intermediate: ¹NMR (CDCl₃) δ0.90 (q, 6H), 1.05-2.0 (m, 19H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H),3.4 (t, 1H), 3.9 (t, 2H), 4.1 (d, 1H), 5.18 (s, 4H), 5.42 (s, 1H), 5.95(s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.2-7.4 (m, 12H), 7.85 (d, 1H).

[0772] Step 3: Preparation of diacid

[0773] A suspension of 0.539 g (0.664 mmol) of the dibenzyl esterintermediate (obtained from Step 2) and 25 mg of 10% Pd/C in 30 mL ofethanol was agitated at ambient temperature under 20 psi of hydrogen gasfor 2 hours. The catalyst was filtered off, and the filtrate wasconcentrated to give the desired title compound as a solid: mp 118° C.;¹NMR (CDCl₃) δ 0.9 (d, 6H), 1.05-2.2 (m, 20H), 2.8 (s, 6H), 3.0 (q, 2H),3.4 (s, 1H), 3.95 (s, 2H), 4.1 (s, 1H), 5.42 (s, 1H), 5.95 (s, 1H), 6.5(d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.85 (d, 1H). HRMS. Calc'd forC₃₄H₄₉NO₈S: 632.3257. Found: 632.3264. Anal. Calc'd for C₃₄H₄₉NO₈S: C,64.63; H, 7.82; N, 2.22; S, 5.08. Found: C, 63.82; H, 7.89; N, 2.14; S,4.93.

EXAMPLE 1414

[0774]

[0775](4R-cis)-3,3-Dibutyl-5-[4-[[5-(diethylamino)pentyl]oxy]phenyl]-7-(dimethylamino)-2,3,4,5-tetrahydro-1-benzothiepin-4-ol1,1-dioxide

[0776] Step 1: Preparation of pentyl iodide intermediate

[0777] To a solution of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide(3 g, 6.53 mmol, obtained from Example 1402, Step 10) in 100 mL ofdimethylformamide was added 198 mg (7.83 mmol) of 95% sodium hydride.The mixture was stirred 15 minutes at room temperature and diiodopentanewas added. After one hour at room temperature the mixture was diluted inethyl acetate and water. The aqueous layer was extracted with ethylacetate and the combined organic layer was washed with brine, dried overmagnesium sulfate and concentrated in vacuo. The residue waschromatographed over silica gel, eluting with hexane/ethyl acetate (1/5)to afford 2.92 g (4.46 mmol) of the pentyl iodide intermediate: ¹NMR(CDCl₃) δ 0.9 (m, 6 H), 1-1.5 (m, 11 H), 1.6 (m, 3 H), 1.8 (m, 4 H), 2.2(m, 1 H), 2.8 (s, 6 H), 3.0 (d, J=15 Hz, 1 H), 3.2 (d, J=15 Hz, 1 H),3.3 (m, 2 H), 4.0 (m, 1 H), 4.1 (s, 1 H), 5.5 (s, 1 H), 6.1 (s, 1 H),6.6 (m, 1 H), 6.9 (d, J 9 Hz, 2 H), 7.4 (d, J=9 Hz, 2 H), 7.9 (d, J=7Hz, 1 H).

[0778] Step 2: Preparation of amine

[0779] A solution of 550 mg (0.76 mmol) of the pentyl iodideintermediate (obtained from Step 1) and 279 mg (3.81 mmol) ofdiethylamine in 3 mL of acetonitrile was stirred at 100° C. overnight.The mixture was concentrated in vacuo to yield a yellowish brown foam.The foam was dissolved in 10 mL of ethyl acetate and washed with 50 mLof saturated sodium carbonate solution twice. The ethyl acetate layerwas dried over magnesium sulfate and concentrated to yield 390 mg (85%)of the desired title compound as a yellow foamy solid: ¹NMR (CDCl₃) δ0.89 (m, 6H), 1.20-1.47 (m, 12H), 1.53-1.67 (m, 4H), 1.76-1.90 (m, 8H),2.21 (m, 1H), 2.74-2.92 (m, 12H), 3.07 (ABq, 2H), 4.00 (t, J=6.3 Hz,2H), 4.10 (d, J=7.8 Hz, 1H), 5.48 (s, 1H), 6.00 (d, J=2.4 Hz, 1H), 6.51(dd, J=9.2 Hz, 2.6 Hz, 1H), 6.92 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.4 Hz,2H), 7.90 (d, J=9.0 Hz, 1H).

EXAMPLE 1415

[0780]

[0781](4R-cis)-N-(Carboxymethyl)-N-[5-[4-[3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yllphenoxylpentyl]glycine

[0782] Step 1: Preparation of diester intermediate

[0783] A mixture of 8.6 g (14.1 mmol) of pentyl bromide intermediate(obtained from Example 1413, Step 1), 65 g (0.35 mol) ofdiethylaminodiacetate and 7.5 g (71 mmol) of anhydrous Na₂CO₃ wasstirred at 160° C. for 3 hours. The reaction mixture was diluted withwater and extracted with methylene chloride. The volatiles was removedin vacuo to give 9.6 g (95%) of the diester intermediate. ¹NMR spectrumwas consistent with the structure; MS (M+H) m/e 717.

[0784] Step 2: Preparation of diacid

[0785] The mixture of the diester intermediate (obtained from Step 1)and 2.7 g (64.3 mmol) of LiOH in THF (75 mL) and water (50 mL) wasstirred at 40° C. for 18 hours. The reaction mixture was acidified with1% HCl and extracted with dichloromethane. The residue was trituratedwith hexane, filtered to give 8.9 g (93%) of the desired title compoundas a solid: mp 148-162° C.; ¹H NMR (CD₃OD) δ 0.92 (t, 6H), 1.1-1.9 (m,31H), 2.15 (t, 1H),2.8(s, 6H), 3.15 (ABq, 2H), 3.75(m, 1H), 4.1 (m, 6H),5.3(s, 1H), 6.1 (s, 1H), 6.6 (d, 1H), 7.0(d, 2H), 7.4 (d, 2H), 7.8 (d,iH); MS (M+H) m/e 661. Anal. Calc'd for [C₃₅H₅₂N₂O₈S+1.5H₂0]: C,61.11;H,8.06; N,4.07; S,4.66. Found: C,61.00; H,7.72; N,3.89; S,4.47.

EXAMPLE 1416

[0786]

[0787] (4R-cis)-5-[4-[[5-[bis[2-(Diethylamino)ethyl]amino]pentyl]oxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-1-benzothiepin-4-ol1,1-dioxide

[0788] A solution of 1 g of pentyl iodide intermediate (1.53 mmol,obtained from Example 1414, Step 1) in N,N,N′,N′-tetraethyldiethylenetriamine was heated to 80° C. for 4 hours. The mixture wasdissolved in ethyl acetate and saturated NaHCO₃. The organic layer waswashed with brine, dried over magnesium sulfate, and concentrated invacuo. The residue was purified by reverse phase chromatography. Thefractions containing the product were concentrated in vacuo, dissolvedin ethyl acetate and washed with saturated NaHCO₃. The residue was driedand concentrated in vacuo to afford 840 mg (74%) of the desired titlecompound as a thick oil. ¹H NMR (CDCl₃) δ 0.8 (m, 6 H), 1-1.6 (m, 28 H),1.8 (m, 2 H), 2.1 (m, 1 H), 2.5 (m, 18 H), 2.7 (s, 6 H), 2.9 (d, J=15Hz, 1 H), 3.1 (d, J=15 Hz, 1 H), 3.9 (m, 2 H), 4.0 (m, 1 H), 4.1 (s, 1H), 5.4 (s, 1 H), 6.0 (s, 1 H), 6.4 (m, 1 H), 6.9 (d, J=9 Hz, 2 H), 7.4(d, J=9 Hz, 2 H), 7.8 (d, J=7 Hz, 1 H). MS (M+H) m/e 743.

EXAMPLE 1417

[0789]

[0790] (4R-cis) -3,3-Dibutyl-7-(di,ethylamino)-2,3,4,5-tetrahydro-5-[4-[[5-[[2-(lH-irnidazol-4-yl)ethyl]amino]pentyl]oxy]phenyl]-1-benzothiepin-4-ol1,1-dioxide

[0791] A solution of 1 g of pentyl iodide intermediate (1.53 mmol,obtained from Example 1414, Step 1) and 3.4 g (30.6 mmol) of histaminewas heated to 50° C. for 17 hours. The mixture was dissolved in ethylacetate and saturated NaHCO₃. The organic layer was washed with brine,dried over magnesium sulfate, and concentrated in vacuo. The residue wastriturated with ether to afford 588 mg (60%) of the desired titlecompound as a semi-solid: ¹H NMR (CDCl₃) δ 0.9 (m, 6 H), 1-1.7 (m, 14H), 1.9 (m, 3 H), 2.0 (m, 2 H), 2.2 (m, 1 H), 2.8 (s, 6 H), 3.0 (m, 3H), 3.2 (m, 2 H), 4.0 (m, 2 H), 4.1 (m, 3 H), 5.5 (s, 1 H), 6.0 (s, 1H), 6.5 (m, 1 H), 6.8 (s, 1 H), 6.9 (d, J=9 Hz, 2 H), 7.4 (m, 3 H), 7.9(d, J=8 Hz, 1 H). MS (M+H) m/e 639.

EXAMPLE 1418

[0792]

[0793](4R-cis)-N-[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxylpentyl]-N′-ethyl-N,N,N′,N′-tetramethyl-1,2-ethanediaminiumdichloride

[0794] Step 1: Preparation of pentyl bromide intermediate

[0795] A mixture of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide(1.680 g, 3.66 mmol, obtained from Example 1402, Step 10) and sodiumhydride (0.250 g, 6.25 mmol) in 30 mL of DMF was stirred in a dry 100 mLround-bottom flask under N₂. To this solution was added1,5-dibromopentane (6.0 mL/44.0 mmol), and the resulting mixture wasstirred for 18 hours. The reaction was diluted with brine (100 mL) andH₂0 (20 mL), and the mixture was extracted with EtOAc (3x50 mL). Organiclayers were combined, dried (MgSO₄), filtered and concentrated in vacuo.Purification by filtration through silica gel eluting with 20%EtOAc/hexane and evaporation in vacuo gave pentyl bromide intermediateas a white foamy solid (1.783 g, 80%): ¹NMR (CDCl₃) δ 0.84-0.95 (m, 6H),1.02-1.56 (m, 10H), 1.58-1.70 (m, 3H), 1.78-2.03 (m, 4H), 2.15-2.24 (m,1H), 2.77 (s, 1H), 2.80 (s, 6H), 3.05 (ABq, 2H), 3.42 (t, 2H), 3.98 (t,2H), 4.10 (s, iH), 5.47 (s, 1H), 5.99 (d, 1H), 6.50 (dd, 1H), 6.91 (d,2H), 7.40 (d, 2H), 7.88 (d, 1H).

[0796] Step 2: Preparation of mono-quaternary salt

[0797] The mixture of pentyl bromide intermediate (0.853 g, 1.40 mmol,obtained from Step 1), N,N,N′,N′-tetramethylethylenediamine (1.0 mL/6.62mmol) in 30 mL of acetonitrile was stirred at 40° C. for 12 hours, andthe reaction mixture was concentrated in vacuo to give an off-whitefoamy solid (1.052 g). The crude product was dissolved in acetonitrile(1.5 mL) and triturated with ethyl ether. The solvent was decanted toyield a sticky solid. This trituration method was repeated twice, andthe resulting sticky solid was concentrated in vacuo to give themono-quaternary salt as an off-white foamy solid (0.951 g, 94%): ¹H NMR(CDCl₃) δ 0.81 (t, 6H), 0.96-1.64 (m, 13H), 1.62-1.85 (m, 4H), 2.03-2.18(m, 1H), 2.20 (s, 6H), 2.67 (t, 2H), 2.74 (s, 6H), 2.98 (ABq, 2H),3.30-3.42 (m, 1H), 3.38 (s, 6H), 3.60-3.75 (m, 4H), 3.90 (t, 2H), 4.01(s, 1H), 5.37 (s, 1H), 5.92 (s, 1H), 6.41 (dd, 1H), 6.81 (d, 2H), 7.32(d, 2H), 7.77 (d, 1H).

[0798] Step 3: Preparation of di-quaternary salt

[0799] The mono-quaternary salt (0.933 g, 1.29 mmol, obtained from Step2), iodoethane (0.300 mL/3.75 mmol), and acetonitrile (30.0 mL) werecombined in a 4 oz. Fischer Porter bottle. The reaction vessel waspurged with N₂, sealed, equipped with magnetic stirrer, and heated to50° C. After 24 hours, the reaction mixture was cooled to ambienttemperature and concentrated in vacuo to give a yellow foamy solid(1.166 g). The solid was dissolved in methylene chloride/acetonitrileand precipitated with ethyl ether. After cooling to 0° C. overnight, theresulting solid was filtered, washed with ethyl ether and concentratedin vacuo to yield the di-quaternary salt as an off-white solid (1.046 g,92%): ¹NMR (CD₃OD) δ 0.59 (t, 6H), 0.70-1.10 (m, 9H), 1.16 (t, 3H),1.22-1.80 (m, 9H), 2.42 (s, 6H), 2.78 (d, 2H), 2.98 (s, 6H), 3.02 (s,6H), 3.22-3.37 (m, 4H), 3.63-3.78 (m, 4H), 3.80 (s, 4H), 4.93 (s, 1H),5.71 (s, 1H), 6.22 (dd, 1H), 6.61 (d, 2H), 7.02 (d, 2H), 7.40 (d, 1H).

[0800] Step 4: Preparation of quaternary di-chloride salt

[0801] The iodobromosalt (obtained from Step 3) was converted to itscorresponding dichloride salt using Biorad AG 2X8 resin and eluting with70% H₂0/acetonitrile to give the desired title compound as a white foamysolid (0.746 g, 84%): mp 193.0-197.0° C.; ¹H NMR (CD₃OD) δ 0.59 (t,J=6.0 Hz, 6H), 0.70-1.12 (m, 9H), 1.16 (t, J=6.6 Hz, 3H), 1.24-1.90 (m,9H), 2.50 (s, 6H), 2.78 (s, 2H), 3.08 (s, 6H), 3.11 (s, 6H), 3.24-3.50(m, 4H), 3.68 (s, 2H), 3.81 (s, 2H), 4.16 (s, 4H), 5.02 (s, 1H), 5.72(s, 1H), 6.19 (d, J=8.4 Hz, 1H), 6.61 (d, J=8.1 Hz, 2H), 7.10 (d, J=7.8Hz, 2H), 7.46 (d, J-=8.7 Hz, 1H). HRMS. Calc'd for C₃₉H₆₇N₃O₄SCl:708.4541. Found: 708.4598.

EXAMPLE 1419

[0802]

[0803][4R-[4a,5a(4R*,5R*)]]-N,N′-bis[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyll-N,N,N′N′-tetramethyl-1,6-hexanediaminiumdichloride

[0804] The pentyl bromide intermediate (1.002 g, 1.64 mmol, obtainedfrom Example 1418, Step 1) and N,N,N′,N′-tetramethyl-1,6-hexanediamine(0.100 g, 0.580 mmol) in 5 mL of acetonitrile were placed in a 4 oz.Fischer Porter bottle. The reaction vessel was purged with N₂, sealed,equipped with magnetic stirrer and heated to 50° C. After 15 hours, thereaction mixture was cooled to ambient temperature and concentrated invacuo to give an off-white foamy solid (1.141 g). The solid wasdissolved in acetonitrile and precipitated with ethyl ether. Aftercooling to 0° C., the solvent was decanted to yield a sticky off-whitesolid. This trituration method was repeated, and the resulting stickysolid was concentrated in vacuo to give the desired dibromide salt as anoff-white foamy solid (0.843 g, quantitative): ¹NMR (CDCl₃) δ 0.85 (m,12H), 1.01-1.70 (m, 30H), 1.76-2.08 (m, 12H), 2.18 (t, J=12.3 Hz, 2H),2.79 (s, 12H), 3.03 (ABq, 4H), 3.35 (s, 12H), 3.52 (br s, 6H), 3.72 (brs, 4H), 3.97 (br s, 4H), 4.08 (br s, 2H), 5.42 (s, 2H), 6.00 (s, 2H),6.51 (d, J=9.0 Hz, 2H), 6.86 (d, J=7.8 Hz, 4H), 7.38 (d, J=7.8 Hz, 4H),7.83 (d, J=8.7 Hz, 2H). The dibromide salt was converted to itscorresponding dichloride salt using Biorad AG 2X8 resin and eluting with70% H₂O/CH₃CN to give the desired title compound as a white foamy solid(0.676 g, 86%): mp 178.0-182.0° C.; ¹H NMR (CDCl₃) δ 0.80-0.90 (m, 12H),1.01-1.70 (m, 30H), 1.75-2.06 (m, 12H), 2.16 (t, J=12.9 Hz, 2H), 2.79(s, 12H), 3.03 (ABq, 4H), 3.33 (s, 12H), 3.49 (br s, 6H), 3.70 (br s,4H), 3.96 (t, J=5.4 Hz, 4H), 4.08 (s, 2H), 5.42 (s, 2H), 5.986 (s, 1H),5.993 (s, 1H), 6.49 (d, J=9.0 Hz, 1H), 6.50 (d, J=9.0 Hz, 1H), 6.87 (d,J=8.4 Hz, 4H), 7.38 (d, J=8.1 Hz, 4H), 7.84 (d, J=8.7 Hz, 2 H) . HRMS.Calc'd for C₃₆H₅,N₂0₄S: 614.4118. Found: 614.4148.

EXAMPLE 1420

[0805]

[0806](4R-cis)-3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-[4-[[5-(1H-tetrazol-5-yl)pentyl]oxy]phenyl]-l-benzothiepin-4-ol1,1-dioxide

[0807] Step 1: Preparation of pentyl bromide intermediate

[0808] To a stirred suspension of 1.01 g (25.4 mmol, 60% oil dispersion)of sodium hydride in 150 mL of DMF was added 9.0 g (19.5 mmol) of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide(obtained from Example 1402, Step 10) in portions. After 30 minutes thereaction was cooled in a water bath (15° C.) and 4.48 g (195 mmol) of1,5-dibromopropane was added. The reaction was stirred at ambienttemperature for 1.5 hours and quenched with 50 mL of saturated NH₄Cl.The reaction was diluted with ethyl acetate, washed with water, brine,dried over MgSO₄, filtered and concentrated in vacuo. Purification bysilica gel chromatography (Waters-Prep 500) using 25% ethylacetate/hexanes afforded 10.17 g (85%) of the pentyl bromideintermediate as a colorless foam: mp 65-70° C.; ¹NMR (CDCl₃) δ 0.84-0.98(M, 6H), 1.04-1.52 (m, lOH), 1.58-1.65 (m, 3H), 1.82 (p, J=6.8 Hz, 2H),1.94 (p, J=7.0 Hz, 2H), 2.12-2.26 (m, IH), 2.82 (s, 6H), 3.06 (ABqI JS=15.2, 45.3 Hz, 2H), 3.44 (t, J=6.7 Hz, 2H), 3.99 (t, J=6.3 Hz, 2H),4.10 (s, 1H), 5.47 (s, 1H), 6.15 (d, J=2.7 Hz, 1H), 6.68 (dd, J=2.5, 8.4Hz, 1H), 6.91 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.93 (d, J=8.7Hz, 1H).

[0809] Step 2: Preparation of pentyl nitrile intermediate

[0810] To a stirred solution of 378 mg (0.621 mmol) of the pentylbromide intermediate (obtained from Step 1) in 1 mL of DMSO was added 37mg (0.745 mmol) of sodium cyanide. The reaction was stirred at ambienttemperature for 16 hours. The reaction was concentrated under a nitrogenstream and the residue partitioned between ethyl acetate and water. Theorganic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated in vacuo to afford 278 mg (93% RPHPLC purity, ca. 75%) ofthe pentyl nitrile intermediate as a colorless foam: ¹H NMR (CDCl₃) δ0.0.86-0.96 (m, 6H), 1.02-1.21(m, 1H), 1.21-1.52 (m, 19H), 1.58-1.92 (m,7H), 2.16-2.28 (m, 1H), 2.41 (t, J=6.9 Hz, 2H), 2.83 (s, 6H), 3.08 (ABqr15.0, 47.5 Hz, 2H), 4.01 (t, J=6.2 Hz, 2H), 4.1 (S, 1H), 5.49 (s, 1H),6.07 (d, J=2.1 Hz, 1H), 6.59 (dd, J=2.4, 8.7 Hz, 1H), 6.92 (d, J=8.1 Hz,2H), 7.42 (d, J=8.4 Hz, 2H), 7.92 (d, J=8.7 Hz, 1H). MS (ES, M+H) m/e555.

[0811] Step 3: Preparation of tetrazole

[0812] A solution of 275 mg (0.5 mmol) of the nitrile intermediate(obtained from Step 2) and 666 mg (3.23 mmol) of azidotrimethyltin in 5mL of toluene was stirred with heating at 80° C. for 60 hours. Thereaction was concentrated under a nitrogen stream.

[0813] Purification by reversed phase chromatography (Waters-Delta prep)using 60% water/acetonitrile afforded 226 mg of the desired titlecompound (75%) as a colorless foam: mp 80-85° C.; ¹H NMR (CDCl₃) δ0.83-0.95 (m, 6H), 1.30-1.52 (m, 10H), 1.52-1.73 (m, 3H), 1.79-1.99 (m,4H), 2.14-2.26 (m, 1H), 2.91 (s, 6H), 3.02-3.22 (m, 4H), 3.92-4.06 (m,2H), 4.16 (s, 1H), 5.47 (s, 1H), 6.28 (d, J=2.4 Hz, 1H), 6.74 (dd,J=2.7, 8.8 Hz, 1H), 6.89 (d, J=8.7 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 7.98(d, J=8.7 Hz, 1H). HRMS Calc'd for C₃₂H₄₈N₅O₄S: 598.3427. Found:598.3443.

EXAMPLE 1421

[0814]

[0815](4R-cis)-4-[[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-lbenzothiepin-5-yllphenoxylpentyl]oxy]-2,6-pyridinecarboxylicacid

[0816] Step 1: Preparation of pentyl bromide intermediate

[0817] To a solution of 0.63 g (15.72 mmol, 60% disp) of NaH in 85 mL ofDMF was add 6.0 g (13.1 mmol) of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzo-thiepine-1,1-dioxide(obtained from Example 1402, Step 10), and the resulting solution wasstirred at ambient temperature for 1 hour. To the solution was added37.7 g (163.75 mmol) of 1,5-dibromopentane, and stirred overnight atambient temperature. DMF was removed in vacuo and the residue wasextracted with ethyl acetate and washed with brine. The extract wasdried over MgSO₄, and the concentrated residue was purified by columnchromatography to give the pentyl bromide intermediate: ¹NMR (CDCl₃) δ0.90 (q, 6H), 1.05-2.0 (m, 17H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H),3.4 (t, 2H), 3.95 (t, 2H), 4.1 (s, 1H), 5.42 (s, 1H), 6.0 (s, 1H), 6.5(d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).

[0818] Step 2: Esterification of chelidamic acid

[0819] A solution of 10 g (54.6 mmol) of chelidamic acid, 23.0 g (120.12mmol) of 1-(3-dimethyl amino propyl)-3 ethyl carbodiimide hydrochloride,1.33 g (10.8 mmol) of 4-dimethyl amino pyridine, and 12.4 mL (120.12mmol) of benzyl alcohol in 100 mL of DMF was stirred at ambienttemperature overnight under N₂. DMF was removed in vacuo and the residuewas extracted with methylene chloride, washed with 5% NaHCO₃, 5% aceticacid, H₂O, and brine. The extract was dried over MgSO₄, and theconcentrated residue was purified by column chromatography to givedibenzyl chelidamic ester: ¹NMR (CDCl₃) δ 5.4 (s, 4H), 7.4 (m, 12H).

[0820] Step 3: Preparation of pyridinyl benzyl ester intermediate

[0821] A solution of 79 mg (1.972 mmol, 60% disp) of NaH and 0.716 g(1.972 mmol) of dibenzyl chelidamic ester (obtained from Step 2) in 17.5mL of DMF was stirred at ambient temperature for 1 hour. To the solutionwas added 1.0 g (1.643 mmol) of the pentyl bromide intermediate and themixture was stirred under N₂ overnight at 40° C. DMF was removed invacuo, and the residue was extracted with ethyl acetate and washed withbrine. The extract was dried over MgSO₄, and the concentrated residuewas purified by column chromatography to give the pyridinyl dibenzylester intermediate: ¹NMR (CDCl₃) δ 0.90 (q, 6H), 1.05-2.0 (m, 19H), 2.2(t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 4.0 (t, 2H), 4.1 (s, 1H), 5.4 (s,4H), 5.42 (s, 1H), 6.0 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.3-7.5 (m,12H), 7.78 (s, 2H), 7.9 (d, 1H).

[0822] Step 4: Preparation of pyridinyl diacid

[0823] A suspension of 0.8813 g (0.99 mmole) of dibenzyl ester (obtainedfrom Step 3) and 40 mg of 10% Pd/C in 35 mL of ethanol and 5 mL of THFwas agitated at ambient temperature under 20 psi of hydrogen gas for 2hours. The catalyst was filtered off, and the filtrate was concentratedto give the desired title compound as a solid: mp 143° C.; 1H NMR(THF-d8) 0.95 (q, 6H), 1.05-1.65 (m, 15H), 1.9 (m, 4H), 2.22 (t, 1H),2.8 (s, 6H), 3.0 (t, 2H), 4.1 (s, 3H), 4.3 (s, 2H), 5.4 (s, 1H), 6.05(s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.78 (d, 1H), 7.82 (s,2H). HRMS. Calc'd for C₃₈H₅₀N₂O₉S: 711.3315. Found: 711.3322. Anal.Calc'd for C₃₈H₅₀N₂O₉S: C, 64.20; H, 7.09; N, 3.94; S, 4.51. Found: C,62.34; H, 6.97; N, 4.01; S, 4.48.

EXAMPLE 1422

[0824]

[0825] (4R-cis)-[5-[4-[3, 3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyl]guanidine

[0826] Step 1: Preparation of pentyl azide intermediate

[0827] To a stirred solution of 200 mg (0.328 mmol) of the pentylbromide intermediate (obtained from Example 1420, Step 1) in 0.75 mL ofDMSO was added 32 mg (0.493 mmol) of sodium azide and a catalytic amountof sodium iodide. The reaction was stirred at ambient temperature for 64hours. The reaction was concentrated under a nitrogen stream and theresidue partitioned between ethyl acetate and water. The organic layerwas washed with brine, dried over MgSO₄, filtered, and concentrated invacuo to afford 155 mg (92% RPHPLC purity, about 76% yield) of thepentyl azide intermediate as a colorless foam. Sample was used withoutfurther purification: mp 45-50° C.; ¹NMR (CDCl₃) δ 0.83-0 93 (m, 6H),1.03-1.48 (m, 10H), 1.54-1.74 (m, SH), 1.78-1.86 (m, 1H), 2.14-2.26 (m,1H), 2.81 (s, 6H) , 3.06 (ABq, JA =15.0, 48. 0 Hz, 2H) , 3.31 (t, J=6.3Hz, 2H), 3.98 (t, J=6.3 Hz, 2H), 4.09 (s, 1H), 5.47 (s, 1H), 6.10 (d,J=1.8 Hz, 1H), 6.63 (dd, J=2.7, 9.0 Hz, 1H), 6.91 (d, J=9.0 Hz, 2H),7.39 (d, J=8.4 Hz, 2H), 7.91 (d, J=8.7 Hz, 1H) . MS (FAB, M+H) m/e 571.

[0828] Step 2: Preparation of pentyl amine intermediate

[0829] To a solution of 0.67 g (1.17 mmol) of the azide intermediate(obtained from Step 1) in 75 mL of ethanol was added 0.10 g of 10%palladium on carbon and the mixture shaken under 49 psi of hydrogen atambient temperature for 3.5 hours. The reaction was filtered throughcelite and concentrated in vacuo to give 0.62 g (86% RPHPLC purity, ca.84%) of pentyl amine intermediate as an off-white foam. The sample wasused without further purification: mp 70-85° C.; ¹H NMR (CDCl₃) δ0.86-0.96 (m, 6H), 1.06-1.75 (m, 15H), 1.79-1.93 (m, 4H), 2.15-2.28 (m,1H), 2.82 (s, 6H), 2.96-3.20 (m, 4H), 3.99 (t, J=6.0 Hz, 2H), 4.04-4.14(m, 1H), 5.49 (s, 1H), 6.00 (d, J=1.5 Hz, 1H), 6.51 (d, J=9.0 Hz, 1H),6.91 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.90 (d, J=8.7 Hz, 1H).MS (ES, M+H) m/e 545.

[0830] Step 3: Preparation of guanidine

[0831] To a stirred solution of 258 mg (0.474 mmol) of pentyl aminointermediate (obtained from Step 2) and 81 mg (0.551 mmol) of1H-pyrazole-1-carboxamidine hydrochloride in 1.5 mL of DMF was added 71mg (0.551 mmol) of diisopropylethylamine. The reaction was stirred atambient temperature for 16 hours.

[0832] Purification by reversed phase chromatography (Waters-Delta prep)using 60% water/acetonitrile afforded 120 mg (43%) of the desired titlecompound as colorless foamy solid: mp 67.0-72.5° C.; 1H NMR (CDCl₃) δ0.89-0.93 (m, 6H), 1.05-1.17 (m, 1H), 1.26-1.90 (m, 16H), 2.07-2.24 (m,IH), 2.81 (s, 6H), 2.99-3.19 (m, 4H), 3.98 (br s, 2H), 4.12 (s, 1H),5.46 (s, IH), 6.01 (d, J=2.1 Hz, 1H), 6.51 (dd, J=2.1, 8.0 Hz, 1H), 6.92(d, J=8.1 Hz, 2H), 7.41 (d, J=7.8 Hz, 2H), 7.89 (d, J=8.7 Hz, 1H) .HRMS. Calc'd for C₃₂H₅₀N₄O₄S:586.3552. Found(M+H): 587.3620.

EXAMPLE 1423

[0833]

[0834](4R-cis)-N-[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxylpentyl]glycine

[0835] Step 1: Preparation of pentyl azide intermediate

[0836] To a solution of pentyl bromide intermediate (400 mg, 0.657 mmol,obtained from Example 1420, Step 1) in dimethyl sulfoxide (20 mL) wasadded sodium azide (47 mg, 0.723 mmol, 1.1 eq), and the resulting clearsolution was stirred at 23° C. for 16h. The reaction solution wasdiluted with 100 mL ethyl acetate, then washed with water (2×100 mL) andbrine (lx 100 mL). The organic layer was dried (MgSO₄) and concentratedin vacuo to give 390 mg (quantitative) of pentyl azide intermediate as ayellow oil: ¹NMR (CDCl₃) δ 0.82-0.90 (m, 7H), 1.05-1.56 (m, 12H),1.59-1.71 (m, 3H), 1.78-2.01 (m, 4H), 2.20 (t, J=8.3 Hz, 1H), 2.82 (s,6H), 3.08 (q, 2H), 3.44 (t, J=7.7 Hz, 2H), 3.99 (t, J=7.7 Hz, 2H), 4.91(br s, 1H), 5.47 (s, 1H), 6.13 (d, J=7.58 Hz, 1H), 6.68 (d, J=7.7 Hz,1H), 7.14 (ABq, 4H) , 7.91 (d, U =7.8 Hz, 1H).

[0837] Step 2: Preparation of amino ester intermediate

[0838] A suspension of pentyl azide intermediate (390 mg, 0.684 mmol,obtained from Step 1) and 100 mg of palladium on carbon in ethanol (15mL) was agitated under an atmosphere of hydrogen gas (48 psi) for 4.5hours. The ethanolic suspension was filtered through celite andconcentrated in vacuo to give a yellow oil. The oil was immediatelydiluted with acetonitrile (15 mL), followed by the addition oftriethylamine (0.156 g, 1.54 mmol, 2.25 eq) and bromo acetic acid benzylester (0.212 g, 0.925 mmol, 1.35 eq). The reaction was stirred at 23° C.for 48 hours. The reaction was concentrated in vacuo, and the residuewas dissolved in ethyl acetate (20 mL) and washed with water (2×20 mL)and brine (1×20 mL). The organic layer was dried (MgSO₄) and dried invacuo to give 420 mg (89%) of the amino ester intermediate as a yellowoil: ¹H NMR (CDCl₃) δ 0.82-0.90 (m, 6H), 1.05-1.56 (m, 14H), 1.58-1.71(m, 3H), 1.78-2.01 (m, 4H), 2.20 (t, J=8.3 Hz, 1H), 2.75 (d, J=7.83 Hz,1H), 2.795 (s, 6H), 3.08 (q, 2H), 3.68-3.85 (m, 2H), 3.87-4.04 (m, 2H),4.09 (s, 1H), 5.147 (s, 1H), 5.46 (s, 1H), 5.98 (d, J=7.58, 1H), 6.50(dd, 1H), 6.85-6.87 (m, 2H), 7.28-7.45 (m, 5H), 7.89 (d, J=8.0 Hz, 1H).MS (ES) m/e 693.

[0839] Step 3: Preparation of acid

[0840] A suspension of benzyl ester intermediate (0.420 g, 0.61 mmol,obtained from Step 2) and 100 mg of palladium on carbon in ethanol (15mL) was agitated under an atmosphere of hydrogen gas (48 psi) for 16 h.The suspension was filtered through celite, and concentrated in vacuo togive 0.330 g of a yellow semi-solid. The material was triturated withdiethyl ether =and the remaining semi-solid was dried in vacuo to give0.19 g (52%) of the desired title compound as a yellow semi solid: ¹NMR(CDCl₃) δ 0.86 (br s, 7H), 1.0-1.72 (m, 18H), 1.79 (br s, 2H), 1.98 (s,2H), 2.09-2.24 (m, 2H), 2.78 (s, 6H), 2.99 (q, 2H), 3.96 (bs, 2H), 4.08(s, 1H), 5.46 (s, 1H), 5.97 (s, 1H), 6.40-6.49 (m, 1H), 7.14 (ABq, 4H),7.85 (t, J=7.93 Hz, 1H). MS (ES) m/e 603.

EXAMPLE 1424

[0841]

[0842](4R-cis)-4-[[4-[3,3-Dibutyl-7-(dinethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxylmethyllbenzoicacid

[0843] Step 1: Preparation of benzoate intermediate

[0844] To a solution of 0.53 g (1.15 mmol) of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzo-thiepine-1,1-dioxide(obtained from Example 1402, Step 10) in 10 mL dimethylformamide wasadded 35 mg (1.39 mmol) of 95% sodium hydride and stirred for 10minutes. To the reaction mixture was added 525 mg (2.29 mmol) methyl4-(bromomethyl)benzoate and stirred for 16 hours. Water was added to thereaction mixture, extracted with ethyl acetate, washed with brine, driedover magnesium sulfate, filtered and the solvent evaporated to afford0.51 g (73%) of the benzoate intermediate: ¹NMR (CDCl₃) δ 0.86-0.96 (m,6H), 1.14-1.47 (m, 10H), 1.60-1.64 (m, 1H), 2.20-2.23 (m, 1H), 2.80 (s,6H), 2.99 (d, J=15.1 Hz, 1H), 3.15 (t, J=15.1 Hz, 1H), 3.92 (s, 3H),4.09-4.15 (m, 1H), 5.17 (s, 2H), 5.49 (s, 1H), 5.94 (d, J=2.2 Hz, 1H),6.50 (dd, J=8.9, 2.6 Hz, 1H), 7.00 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.5 Hz,2H), 7.53 (d, J=8.5 Hz, 2H), 7.93 (d, J=8.9 Hz, 1H), 8.06 (d, J=8.5 Hz,2H).

[0845] Step 2: Preparation of acid

[0846] A solution of 0.51 g (0.84 mmol) of the benzoate intermediate(obtained from Step 1) and 325 mg (2.53 mmol) of KOSi(CH₃)₃ (Aldrich) in16 mL THF was stirred for 3.5 hours. The THF was evaporated, wateradded, extracted with ethyl acetate, dried over magnesium sulfate,filtered and the solvent evaporated to afford 0.30 g (60%) of thedesired title compound as a white solid: mp 156 - 159° C.; ¹NMR (CDCl₃)δ 0.89-0.94 (m, 6H), 1.24-1.43 (m, 10H), 1.62-1.66 (m, 1H), 2.20-2.24(m, 1H), 2.84 (s, 6H), 3.02 (d, J=15.1 Hz, 1H), 3.17 (d, J=15.1 Hz, 1H),4.14 (s, 1H), 5.20 (s, 2H), 5.50 (S, 1H), 6.16 (s, 1H), 6.71 (d, J=9.1Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.3Hz, 2H), 7.95 (d, J=8.9 Hz, 1H), 8.13 (d, J=8.1 Hz, 2H) . HRMS. Calc'dfor C3₄H₄₄NO₆S: 594.2889. Found: 594.2913.

EXAMPLE 1425

[0847]

[0848](4R-cis)-1-[[4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-pyridiniumchloride

[0849] Step 1: Preparation of chlorobenzyl intermediate

[0850] A solution of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide(5.0 g, 10.9 mmol, obtained from Example 1402, Step 10) in acetone (100mL) at 25° C. under N₂ was treated with powdered K₂CO₃ (2.3 g, 16.3mmol, 1.5 eq.) and α,α′-dichloro-p-xylene (6.7 g, 38.1 mmol, 3.5 eq.)and the resulting solution was stirred at 65° C. for 48 hours. Thereaction mixture was cooled to 25° C. and concentrated to ⅕ of originalvolume. The residue was dissolved in EtOAc (150 mL) and washed withwater (2×150 mL). The aqueous layer was extracted with EtOAc (2×150 mL)and the combined organic extracts were washed with saturated aqueousNaCl (2×150 mL. The combined extracts were dried (MgSO₄) andconcentrated in vacuo to provide a yellow oil. Purification by flashchromatography (5.4×45 cm silica, 25-40% EtOAc/hexane) afforded thechlorobenzyl intermediate (4.7 g, 72%) as a white foam: ¹NMR (CDCl₃) δ0.89-0.94 (m, 6H), 1.12-1.48 (br m, 10H), 1.63 (m, 1H), 2.22 (m, 1H),2.81 (s, 6H), 3.05 (ABq, J=15.1 Hz, J=50.0 Hz, 2H), 4.11 (d, J=8.1 Hz,1H), 4.60 (s, 2H), 5.11 (s, 2H), 5.48 (s, 1H), 5.96 (d, J=2.4 Hz, 1H),6.48 (dd, J=8.9, 2.6 Hz, 1H), 7.00 (d, J=8.9 Hz, 2H), 7.36-7.47 (m, 5H),7.85 (d, J=8.9 Hz, 1H).

[0851] Step 2: Preparation of quaternary salt

[0852] A solution of the chlorobenzyl intermediate (1.0 g, 1.7 mmol,obtained from Step 1) in acetonitrile (5 mL) at 25° C. under N₂ wastreated with pyridine (5 mL) and stirred at 35° C. for 36 hours. Thepale amber solution was cooled to 25° C. and concentrated in vacuo togive the desired title compound (1.08 g, 96%) as a yellow solid: mp154-156° C.; ¹H NMR (CDCl₃) δ 0.83 (m, 6H), 1.06-1.44 (br m, 10H), 1.60(m, IH), 2.13 (m, 1H), 2.71 (s, 6H), 3.02 (ABq, J=15.1 Hz, J=28.4 Hz,2H), 4.09 (s, 1H), 5.00 (s, 2H), 5.38 (s, 1H), 5.91 (d, J=2.4 Hz, 1H),6.26 (s, 2H), 6.41 (dd, J=8.9, 2.4 Hz, 1H), 6.91 (d, J=8.7 Hz, 2H), 7.26(m, 1H), 7.40 (d, J=7.7 Hz, 4H), 7.73 (d, J=7.9 Hz, 2H), 7.78 (d, J=8.9Hz, 2H), 7.93 (t, J=6.8 Hz, 1H), 8.34 (t, J=7.7 Hz, 1H), 8.58 (br s,1H), 9.69 (d, J=5.8 Hz, 2H); HRMS. Calc'd for C₃₉H₄₉N₂O₄S: 641.3413.Found: 641.3425.

EXAMPLE 1426

[0853]

[0854] (4R-cis)-1-[4-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-4-aza-1-azoniabicyclo[2.2.2]octanechloride

[0855] Under N₂, a solution of 8.7 g (14.5 mmol) of the chlorobenzylintermediate (obtained from a procedure similar to the one outlined inExample 1425, Step 1) in 60 mL of acetonitrile was added dropwise over a30 min period to a solution of 2.9 g (26.2 mmol) ofdiazabicyclo[2.2.2]octane (DABCO) in 40 mL of acetonitrile at 35° C.;during the addition, a colorless precipitate was formed. The slurry wasstirred at 35° C. for an additional 2 h. The product was collected andwashed with 1 L of acetonitrile to give 9.6 g (93%) the title compoundas a colorless crystalline solid: mp 223-230° C. (decomposed); ¹H NMR(CDCl₃) δ 0.89 (m, 6H), 1.27-1.52 (br m, 10H), 1.63 (m, 1H), 2.20 (m,1H), 2.81 (s, 6H), 3.06 (ABq, J 15.1 Hz, J=43.3 Hz, 2H), 3.16 (s, 6H),3.76 (s, 6H), 4.11 (d, J=7.7 Hz, 1H), 5.09 (s, 2H), 5.14 (s, 2H), 5.48(s, 1H), 5.96 (s, 1H), 6.49 (d, J 8.9 Hz, 1H), 6.99 (d, J=8.0 Hz, 2H),7.26 (m, 1H), 7.44 (d, J 8.0 Hz, 2H), 7.52 (d, J=7.4 Hz, 2H), 7.68 (d, J7.4 Hz, 2H), 7.87 (d, J=8.9 Hz, 1H); HRMS. Calc'd for C₄₀H₅₆N₃O₄S:674.3992. Found: 674.4005.

EXAMPLE 1426a

[0856]

[0857](4R-cis)-1-[[4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyll-4-aza-1-azoniabicyclo[2.2.2]octanechloride

[0858] A solution of the chlorobenzyl intermediate (4.6 g, 7.7 mmol,obtained from Example 1425, Step 1) in acetonitrile (100 mL) at 25° C.under N₂ was treated with diazabicyclo[2.2.2]-octane (DABCO, 0.95 g, 8.5mmol, 1.1 eq.) and stirred at 35° C. for 2 hours, during which time awhite solid precipitated out. The white solid was collected, washed withCH₃CN and recrystallized from CH₃0H/Et₂O to give the title compound(4.95 g, 91%) as a white solid: mp 223-230° C. (decomposed); ¹NMR(CDCl₃) δ 0.89 (m, 6H), 1.27-1.52 (br m, 10H), 1.63 (m, 1H), 2.20 (m,1H), 2.81 (s, 6H), 3.06 (ABq, J=15.1 Hz, J=43.3 Hz, 2H), 3.16 (s, 6H),3.76 (s, 6H), 4.11 (d, J=7.7 Hz, 1H), 5.09 (s, 2H), 5.14 (s, 2H), 5.48(s, 1H), 5.96 (s, 1H), 6.49 (d, J=8.9 Hz, 1H), 6.99 (d, J=8.0 Hz, 2H),7.26 (m, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.52 (d, J=7.4 Hz, 2H), 7.68 (d,J=7.4 Hz, 2H), 7.87 (d, J=8.9 Hz, 1H); HRMS. Calc'd for C₄₀Hs₆QO₄S:674.3992. Found: 674.4005.

EXAMPLE 1427

[0859]

[0860]4R-cis)-N-(Carboxymethyl)-N-[[4-[[4-[3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxylmethyllphenyl]methyl]glycine

[0861] Step 1: Preparation of chlorobenzyl intermediate

[0862] To a stirred solution of 144 mg (3.59 mmol, 60% disp) of NaH in29 mL of DMF was added 1.5 g (3.26 mmol) of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetra-hydrobenzothiepine-1,1-dioxide(obtained from Example 1402, Step 10), and the resulting solution wasstirred at ambient temperature for 45 min. To the solution was added7.13 g (40.75 mmol) of dichloro p-xylene, and the mixture was stirredovernight. DMF was removed in vacuo, and the residue was extracted withethyl acetate and washed with brine. The extract was dried over MgSO₄,and the concentrated residue was purified by column chromatography togive the chlorobenzyl intermediate: ¹H NMR (CDCl₃) δ 0.90 (q, 6H),1.05-1.65 (m, 11H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 4.1 (d, 1H),4.6 (s, 2H), 5.1 (s,2H), 5.5 (s, IH), 6.0 (s, 1H), 6.6 (d,1H), 7.0 (d,2H), 7.4 (m, 6H), 7.8 (d,1H).

[0863] Step 2: Preparation of amino diester

[0864] A mixture of 1.03 g (1.72 mmol) of chlorobenzyl intermediate(obtained from Step 1), 1.63 g (8.6 mmol) of diethyl amino diacetate,and 0.72 g (8.6 mmol) of NaHCO₃ in 30 mL of DMF was stirred at 100° C.for 6 hours. DMF was removed in vacuo and the residue was extracted withether and washed with brine. The extract was dried over MgSO₄, and theconcentrated residue was purified by column chromatography to give aminodiester intermediate: ¹NMR (CDCl₃) δ 0.90 (q, 6H), 1.05-1.65 (m, 17H),2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 3.55 (s, 4H), 3.95 (s, 2H),4.1-4.2 (m, 5H), 5.05 (s, 2H), 5.42 (s, 1H), 5.95 (s, 1H), 6.5 (d, 1H),7.0 (d, 2H), 7.4 (s, 6H), 7.8 (d, 1H).

[0865] Step 3: Preparation of amino diacid

[0866] A solution of 0.863 g (1.15 mmol) of dibenzyl ester (obtainedfrom Step 2) and 0.232 g (5.52 mmol) of LiOH in 30 mL of THF and 30 mLof water was stirred at 40° C. under N₂ for 4 hours. The reactionmixture was diluted with ether and washed with 1% HCl. The aqueous layerwas extracted twice with ether, and the combined extracts were washedwith brine, dried over MgSO₄, and concentrated in vacuo to give thedesired title compound as a solid: mp 175° C.; ¹NMR (THF-d8) 0.95 (q,6H), 1.05-1.65 (m, l1H), 2.22 (t, 1H), 2.8 (s, 6H), 3.0 (t, 2H), 3.5 (s,4H), 3.9 (s, 2H), 4.1 (d, 1H), 5.1 (s, 2H), 5.4 (s, 1H), 6.05 (s, 1H),6.5 (d, 1H), 7.0 (d, 2H), 7.4 (m, 6H), 7.78 (d, 1H). HRMS. Calc'd forC₃₈H₅₀N₂O₈S: 695.3366. Found: 695.3359. Anal. Calc'd for C₃₈H₅₀N₂O₈S: C,65.68; H, 7.25; N, 4.03; S, 4.61. Found: C, 64.95; H, 7.32; N, 3.94; S,4.62.

EXAMPLE 1428

[0867]

[0868](4R-cis)-4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1,1-dioxido-1-benzothiepin-5-yllphenoxy]methyl]-1-methylpyridiniumsalt with trifluoroacetic acid (1:1)

[0869] Step 1: Preparation of picolyl intermediate

[0870] To a stirred solution of 12.0 g (26.1 mmol) of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetra-hydrobenzothiepine-1,1-dioxide(obtained from Example 1402, Step 10) in 200 mL of DMF was added 1.4 g(60% oil dispersion, 35 mmol) of sodium hydride and the reaction stirredat ambient temperature for one hour. 5.99 g (36.5 mmol) of 4-picolylchloride hydrochloride was treated with cold saturated NaHCO, solutionand extracted with diethyl ether. The ethereal extracts were washed withbrine, dried over MgSO₄, and filtered. The reaction was cooled in an icebath and the solution of 4-picolyl chloride in diethyl ether was added.The reaction was stirred at ambient temperature for 17 hours. Thereaction was quenched with 25 mL of saturated NH₄Cl, diluted with 600 mLethyl acetate washed with 4X250 mL water, brine, dried over MgSO₄,filtered and concentrated in vacuo. Purification by silica gelchromatography (Waters-prep 500) using 60% ethyl acetate/hexanesafforded 11.05 g (77%) of the picolinyl intermediate as a colorlesssolid: mp 95-98° C.; ¹NMR (CDCl₃) δ 0.86-0.96 (m, 6H), 1.02-1.52 (m,lOH), 1.58-1.70 (m, 1H), 2.16-2.29 (m, 1H), 2.81 (s, 6H), 3.07 (ABq, Ja=15.3, 49.6 Hz, 2H), 4.10 (d, J=7.5 Hz, 1H), 5.15 (s, 2H), 5.50 (s, 1H),5.94 (d, J=2.7 Hz, 1H), 6.51 (dd, J=2.4, 8.7 Hz, 1H), 7.00 (d, J=9.0 Hz,2H), 7.39 (d, 6.0 Hz, 2H), 7.44 (s, J=8.7 Hz, 2H), 7.89 (d, J=9.0 Hz,2H), 8.63 (dd, J=1.6, 4.8 Hz, 2H).

[0871] Step 2: Preparation of quaternary salt

[0872] To a stirred solution of 0.41 g (0.74 mmol) of picolinylintermediate (obtained from Step 1) in 10 mL of acetonitrile and 3 mL ofdichloromethane was added 137 mg (0.97 mmol) of iodomethane. Thereaction was stirred at ambient temperature for 16 hours, thenconcentrated under a nitrogen stream. Purification by reversed phasechromatography (Waters-Delta prep) using 60-55% water/acetonitrileafforded 0.304 g (60%) of the desired title compound as a colorlesssolid: mp 96-99 ° C.; ¹H NMR (CDCl₃) δ 0.85-0.95 (m, 6H), 1.03-1.52 (m,10H), 1.57-1.70 (m, 1H), 2.12-2.27 (m, 1H), 2.84 (s, 6H), 3.09 (ABqf Js=15.0, 27.9 Hz, 2H), 4.11 (s, 1H), 4.46 (s, 3H), 5.37 (s, 2H), 5.50 (s,1H), 6.07 (d, J=2.4 Hz, 1H), 6.61 (dd, J=2.5, 8.7 Hz, 1H), 7.02 (d,J=8.7 Hz, 2H), 7.48 (d, J=7.2 Hz, 2H), 7.90 (d, J=8.7 Hz, 1H), 8.14 (d,J=6.3 Hz, 2H), 8.80 (d, J=6.6 Hz, 2H). HRMS Calc'd for C₃₃H₄,N₂0₄S:565.3100. Found: 565.3125.

EXAMPLE 1429

[0873]

[0874](4R-cis)-4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]-1-methylpyridinium,methanesulfonate (salt)

[0875] To a stirred solution of 6.5 g (11.8 mmol) of picolylintermediate (obtained from Example 1428, Step 1) in 140 mL ofacetonitrile heated at 70° C. was added 1.56 g (14.6 mmol)methanesulfonic acid methyl ester. Heating was continued at 70° C. for15 hours. The reaction was cooled and diluted with 50 mL of ethylacetate. The solid was collected by vacuum filtration to give 6.14 g(79%). The filtrate was concentrated in vacuo and the residuecrystallized from hot acetonitrile to give 1.09 g (14%). A total of 7.23g (93%) of the desired title compound was obtained as an off-whitesolid: mp 232-233.5° C.; ¹NMR (CDCl₃) δ 0.66-0.76 (m, 6H), 0.85-0.95 (m,1H), 0.95-1.35 (m, 9H), 1.42- 1.54 (m, 1H), 1.95-2.22 (m, 1H), 2.50 (s,1H), 2.56 (s, 3H), 2.63 (s, 6H), 2.91 (ABqr J=16.5, 24.0 Hz, 2H), 3.88(s, 1H), 4.40 (s, 3H), 5.21 (s, 3H), 5.78 (d, J=2.4 Hz, 1H), 6.31 (dd,J=2.5, 8.7 Hz, 1H), 6.84 (d, J=8.7 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.64(d, J=8.7 Hz, 1H), 8.0 (d, J=6.6 Hz, 2H), 9.02 (d, JL=6.6 Hz, 2H). HRMSCalc'd for C₃₃H₄₅N₂O₄S: I565.3100. Found: 656.3087. Anal. Calc'd forC₃₄H₄₈N₂O₇S₂: C, 61.79; H, 7.32; N, 4.24; S, 9.70. Found: C, 61.38, H,7.47; N, 4.22; S, 9.95.

EXAMPLE 1430

[0876]

[0877](4R-cis)-6-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]-2-pyridinepropanoicacid

[0878] Step 1: Preparation of picolinyl chloride intermediate

[0879] To a solution of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide(1 g, 2.1 mmol, obtained from Example 1402, Step 10) in acetone (50 mL)was added anhydrous K₂CO₃ (0.45 g, 3.2 mmol), tetrabutylammonium iodide(0.1 g, 0.2 mmol) and 2,6-bischloromethylpyridine (1.2 g, 10.8 mmol).The flask was equipped with nitrogen gas adapter and magnetic stirrer.The reaction was heated to reflux Ifor overnight. After 18 hours, thereaction was diluted with ether and washed with water and brine (30 ML).The organic layers were dried over MgSO₄, filtered and concentrated invacuo. Chromatographic purification through silica gel, eluting with 25%EtOAc/Hexane gave 0.75 g (55%) of the picolyl chloride intermediate asan oil (0.70 g, 55%): ¹H NMR (CDCl₃) δ 0.84-0.95 (m, 6H), 1.02-1.5 (m,10H), 1.56-1.66 (m, 1H), 2.14-2.24 (m, 1H), 2.80 (s, 6H) 3.05 (ABq, 2H),4.10 (d, 2H), 4.65 (s, 2H), 5.20 (s, 2H), 5.45 (s, 1H), 5.95 (s, 1H),6.50 (d, 1H), 7.0 (d, 2H),7.35-7.50 (m, 4H), 7.70-7.85 (m, 2H).

[0880] Step 2: Preparation of pyridinyl malonate intermediate

[0881] Dibenzyl malonate (1.42 g, 5.01 mmol) in DMF (20.0 ml) and sodiumhydride (0.13 g, 3.3 mmol) were placed in a dry three-neck flask. Theflask was equipped with nitrogen gas adapter and magnetic stirrer. Thepicolyl chloride intermediate (lg, 1.67 mmol) was added and heated at90° C. for overnight. The reaction was cooled and extracted with 5% HC1with methylene chloride and washed with water (25 mL), and brine (50mL). The organic layers were dried over MgSO₄, filtered andconcentrated. The residue was purified by C-18 reversed phase columneluting with 50% acetonitrile/water and gave pyridinyl malonateintermediate as a white foamy solid (lg, 71%): ¹NMR (CDCl₃) δ 0.84-0.95(m, 6H), 1.02-1.5 (m, 10H), 1.56-1.66 (m, IH), 2.14-2.24 (m, 1H), 2.80(s, 6H) 3.05 (ABq, 2H), 3.22 (d, 2H), 4.05 (d, 1H), 4.16 (t, 1H),5.02(s, 2H), 5.08 (s, 4H), 5.44 (s, 1H), 5.97 (s, 1H), 6.96-7.10 (m,3H), 7.20-7.32 (m, 12H), 7.5 (t, 1H), 7.9 (d, 1H).

[0882] Step 3: Preparation of pyridinyl acid

[0883] The pyridinyl malonate intermediate (0.6 g, 0.7 mmol, obtainedfrom Step 2), THF/water (25.0 mL, 1:1) and lithium hydroxide monohydrate(0.14 g, 3.4 mmol) were placed in a 100 mL round-bottom flask. Thereaction was stirred at ambient temperature overnight. After 18 hours,the reaction was extracted with 1% HCl and ether and then washed withwater (20 mL) and brine (30 mL). The organic layers were dried overMgSO₄, filtered and concentrated in vacuo gave the desired titlecompound as a white solid (0.44 g, 90%): mp 105-107° C.; ¹NMR (CDCl₃) δ0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H), 1.56-1.66 (m, 1H), 2.14-2.24 (m,1H), 2.80 (s, 6H),3.05 (m, 2H), 3.10 (ABq, 2H), 3.22 (m, 2H), 4.05 (s,1H), 5.30 (s, 2H), 5.50 (s, 1H), 5.97 (s, 1H), 6.50 (d, 1H), 7.02 (d,2H), 7.3 (d, 1H), 7.42 (d, 2H), 7.58 (d, 1H), 7.8-7.9 (m, 2H). HRMS.Calc'd for C₃₅H₄₆N₂O₆S: 623.3155. Found: 623.3188.

EXAMPLE 1431

[0884]

[0885](4R-cis)-N-(Carboxymethyl)-N-[[6-[[4-[3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yllphenoxylmethyl]-2-pyridinyl]methyl]glycine

[0886] Step 1: Preparation of pyridinyl diester intermediate

[0887] A mixture of diethyl aminodiacetate (8 g, 68 mmol) and sodiumcarbonate (0.63 g, 5.9 mmol) was treated with picolyl chlorideintermediate (0.72 g, 1.2 mmol, obtained from Example 1430, Step 1), andstirred at 160° C. for three hours. The reaction was cooled and dilutedwith ether and washed with 1% HCl, water (25 mL), and brine (50 mL). Thecombined extracts were dried over MgSO₄1 filtered and concentrated invacuo. The residue was purified by distillation in the Kugelrohr to givepyridinyl diester intermediate as a yellowish foamy solid (0.72 g, 80%):¹H NMR (CDCl₃) δ 0.84-0.95 (m, 6H), 1.02-1.5 (m, 16H), 1.56-1.66 (m,1H), 2.14-2.24 (m, 1H), 2.80 (s, 6H) 3.05 (ABq, 2H), 3.70 (s, 4H),4.2-4.4 (m, 6H), 5.30 (s, 2H), 5.56 (s, 1H),6.02 (s, 1H), 6.60 (d, 1H),7.10 (d, 2H),7.50 (m, 3H), 7.61 (d, 1H), 7.80 (t, 1H), 7.95 (d, 1H).HRMS. Calc'd for C₄₁H₅₇N₃O₈S: 752.3945. Found: 752.3948.

[0888] Step 2: Preparation of pyridinyl diacid

[0889] A mixture of pyridine-aminodiacetate intermediate (0.7 g, 0.93mmol, obtained from Step 1), and lithium hydroxide monohydrate (0.18 g,4.5 mmol) in THF/ water (25.0 mL, 1:1) was stirred at 40° C. overnight(18 hours). The reaction mixture was diluted with ether and washed with1% HCl, water (20 mL), and brine (30 mL). The organic layers were driedover MgSO₄, filtered and concentrated in vacuo to give the desired titlecompound as a white solid (0.44 g, 90%): mp 153-155° C.; ¹H NMR (CDCl₃)δ 0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H), 1.56-1.66 (m, 1H), 2.14-2.24 (m,1H), 2.80 (s, 6H), 3.10 (ABq, 2H), 3.90 (m, 3H), 4.05 (s, 1H), 4.40 (s,2H), 5.20 (s, 2H), 5.50 (s, 1H), 5.97 (s, 1H), 6.50 (d, 1H), 7.02 (d,2H), 7.3 (d, 1H), 7.42 (d, 2H), 7.58 (d, 1H), 7.8-7.9 (m, 2H). HRMS.Calc'd for C₃₇H₄₉N₃O₈S: 696.3319. Found:696.3331.

EXAMPLE 1432

[0890]

[0891](4S-cis)-[2-[2-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxylethoxy]ethyl]propanedioicacid

[0892] Step 1: Preparation of bromoethyl ether intermediate

[0893] To a stirred solution of 0.192 g (4.785 mmol, 60% disp) of NaH in28 mL of DMF was added 2.0 g (4.35 mmol) of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide(obtained from Example 1402, Step 10), and the resulting solution wasstirred at ambient temperature for 30 min. To the solution was added13.2 g (54.38 mmol) of bis(2-bromoethyl)ether, and stirring wascontinued at ambient temperature under N₂ overnight. DMF was removed invacuo and the residue was extracted with ethyl acetate and washed withbrine. The extract was dried over MgSO₄, and the concentrated residuewas purified by column chromatography to give bromoethyl etherintermediate: ¹NMR (CDCl₃) δ 0.90 (q, 6h), 1.05-1.65 (m, 11H), 2.2 (t,1H), 2.8 (s, 6H), 3.0 (q, 2H), 3.5 (t, 2H), 3.9 (m, 4H), 4.1 (d, 1H),4.2 (d, 2H), 5.42 (s, 1H), 5.95 (s, IH), 6.5 (d, 1H), 6.95 (d, 2H), 7.4(d, 2H), 7.9 (d, 1H).

[0894] Step 2: Preparation of diester intermediate

[0895] To a mixture of 94 mg (2.34 mmol, 60% disp) of NaH in 45 mL ofTHF and 15 mL of DMF at 0° C. was added 1.33 g (4.68 mmol) of dibenzylmalonate (Aldrich), and the resulting solution was stirred at ambienttemperature for 15 min, followed by the addition of 0.95 g (1.56 mmol)of bromoethyl ether intermediate (obtained from Step 1). The mixture wasstirred under N₂ at 80° C. overnight. Solvent was removed in vacuo andthe residue was extracted with methylene chloride and washed with brine.The extract was dried over MgSO₄, and the concentrated residue waspurified by column chromatography to give the diester intermediate: ¹NMR(CDCl₃) δ 0.90 (q, 6H), 1.05-1.65 (m, 11H), 2.2-2.3 (m, 3H), 2.8 (s,6H), 3.0 (q, 2H), 3.6 (t, 2H), 3.7 (m, 3H), 4.1 (m, 3H), 5.1 (s, 4H),5.42 (s, 1H), 5.9 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.3 (m, 10H), 7.4(d, 2H), 7.9 (d, 1H).

[0896] Step 3: Preparation of diacid

[0897] A suspension of 0.761 g (0.935 inmol) of the diester intermediate(obtained from Step 2) and 35 mg of 10% Pd/C in 25 mL of ethanol and 5mL of THF was agitated at ambient temperature under 20 psi of hydrogengas for 2 hours. The catalyst was filtered off, and the filtrate wasconcentrated to give the desired title compound as a solid: mp 119.5°C.; ¹NMR (THF-d8) 0.95 (q, 6H), 1.05-1.65 (m, l1H), 2.1 (q, 2H), 2.25(t, 1H), 2.8 (s, 6H), 3.0 (t, 2H), 3.47 (q, 2H), 3.58 (s, 1H), 3.78 (t,2H), 4.08 (d, 1H), 4.15 (t, 2H), 5.4 (s, 1H), 6.05 (s, 1H), 6.55 (d,1H), 6.98 (d, 2H), 7.42 (d, 2H), 7.8 (d, 1H). HRMS. Calc'd forC₃₃H₄₇NO₉S: 632.2893. Found: 632.2882. Anal. Calc'd for C₃₃H₄₇NO₉S: C,62.54; H, 7.47; N, 2.21; S, 5.06. Found: C, 61.75; H, 7.56; N, 2.13; S,4.92.

EXAMPLE 1433

[0898]

[0899](4R-cis)-a-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxylmethyl]-w-methoxypoly(oxy-1,2-ethanediyl)

[0900] Step 1: Preparation of monomethyl PEG mesylate intermediate

[0901] To a solution of 20 g of monomethyl ether PEG in 100 mL ofmethylene chloride was added 2.2 g (22 mmol) of triethyl amine, and tothe resulting solution at 0° C. was added dropwise 2.5 g (22 mmol) ofmethanesulfonyl chloride. The resulting solution was stirred overnightat ambient temperature, and the triethyl amine hydrochloride wasfiltered off to give the monomethyl PEG mesylate intermediate which wasused in the next Step without further purification and characterization.

[0902] Step 2: Preparation of polyethylene-linked benzothiepene

[0903] A mixture of 38 mg (1.52 mmol 95%) of NaH and 0.7 g (1.52 mmol)of5-(4′-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide(obtained from Example 1402, Step 10) in 5.5 mL of DMF was stirred atambient temperature under N₂ for 30 min. To the solution was added 0.55g (0.51 mmol) of the mesylate PEG intermediate (obtained from Step 1) in5.5 mL of DMF, and the resulting solution was stirred overnight under N₂at 50° C. DMF was removed in vacuo and the residue was extracted withmethylene chloride and washed with brine. The extract was dried overMgSO₄, and the concentrated residue was purified by columnchromatography to give the desired title compound as an oil: ¹NMR(CDCl₃) δ 0.9 (q, 6h), 1.05-1.65 (m, l1H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0(q, 2H), 3.4 (s, 4H), 3.5-3.85 (m, 95H), 4.1 (s, 1H), 4.15 (t, 2H), 5.5(s, 1H), 6.05 (s, 1H), 6.6 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d,1H).

EXAMPLE 1434

[0904] Preparation of:

[0905] The 3-aminobenzothiepene prepared in Step 5 of Example 1398(0.380 g, 0.828 mmol), sodium hydroxide (0.35 mL, 0.875 mmol, 10% inH₂O) and toluene (0.50 mL) were combined in a 10 mL round-bottom flask.The reaction flask was purged with N₂, equipped with magnetic stirrer,and cooled to 0° C. A solution of 3-chloropropyl chloroformate (1.440 g,1.10 mmol, 12% in CH₂Cl₂/ THF) was added. After 3.5 hrs, toluene (3.0mL) was added, and the mixture was washed with H₂O (2×4 mL), dried(MgSO₄), filtered and concentrated in vacuo.

[0906] Purification by flash chromatography on silica gel eluting with20% EtOAc/hexane and concentrated in vacuo gave a white solid (0.269 g,56%). ¹H NMR (CDCl₃) δ 0.87-0.93 (m, 6H), 1.05-1.70 (m, l1H), 2.14 (t,J=6.3 Hz, 2H), 2.15-2.25 (m, 1H), 2.81 (s, 6H), 3.07 (ABq, 2H), 3.64 (t,J=6.3 Hz, 2H), 4.11 (d, J=7.5 Hz, 1H), 4.33 (t, J=6.0 Hz, 2H), 5.50 (s,1H), 5.99 (d, J=2.4 Hz, 1H), 6.51 (dd, J=9.0, 2.7 Hz, 1H), 6.65 (s, 1H),7.23 (d, J=7.8 Hz, 1H), 7.34-7.39 (m, 2H), 7.54 (d, J=7.2 Hz, 1H), 7.89(d, 8.7 Hz, 1H). HRMS (M+H). Calc'd for C₃₀H₄₄N₂O₅SCl: 579.2659. Found:579.2691.

EXAMPLE 1435

[0907] Preparation of:

[0908] 1,4-Diazabicyclo(2.2.2)octane (0.0785 g, 0.700 mmol) andacetonitrile (1.0 mL) were combined in a 10 mL round-bottom flask. Thereaction flask was purged with N₂, equipped with magnetic stirrer, andheated to 37° C. A solution of the product of Example 1434 (0.250 g,0.432 mmol) in acetonitrile (2.50 mL) was added. After 2.5 hrs,1,4-diazabicyclo(2.2.2)octane (0.0200 g, 0.178 mmol) was added. After 64hrs, 1,4-diazabicyclo(2.2.2)octane (0.0490 g, 0.437 mmol) was added.After 24 hrs, the reaction mixture was cooled to R.T. and concentratedin vacuo. The crude product was dissolved in acetonitrile (2.0 mL) andprecipitated with ethyl ether (10.0 mL). The precipitate was filtered toyield a white solid. This trituration method was repeated, followed byconcentrated in vacuo to give a white solid (0.185 g, 62%). mp218.0-225.0° C.; ¹H NMR (CD₃OD) δ 0.90 (m, 6H), 1.05-1.55 (m, 10H), 1.16(t, J=6.6 Hz, 2H), 1.78 (m, 1H), 2.12 (m, 3H), 2.76 (s, 6H), 3.10 (m,2H), 3.17 (t, J=7.2 Hz, 6H), 3.30-3.50 (m, 8H), 4.10 (s, 1H), 4.21 (t,J=5.4 Hz, 2H), 5.31 (s, 1H), 6.10 (s, 1H), 6.55 (d, J=7.2 Hz, 1H), 7.25(d, J=6.9 Hz, 1H), 7.33-7.42 (m, 2H), 7.56 (s, 1H), 7.76 (d, J=9.0 Hz,1H). HRMS. Calc'd for C₃₆H₅₅N₄O₅SCl: 655.3893. Found: 655.3880.

EXAMPLE 1436

[0909] Preparation of:

[0910] Step 1. Preparation of:

[0911] 3-Chloromethylbenzoyl chloride (2.25 mL/15.8 mmol) and acetone(8.0 mL) were combined in a 25 mL round-bottom flask. The reaction flaskwas cooled to 0° C., and an aqueous solution of sodium azide (1.56 g in5.50 mL/24.0 mmol) was added. After 1.5 hrs, the reaction mixture waspoured into ice water (80.0 mL), extracted with ethyl ether (2×25 mL),dried (MgSO₄), and concentrated in vacuo to give a colorless oil (2.660g, 86%). ¹H NMR (CDCl₃) δ 4.62 (s, 2H), 7.47 (t, J=7.8 Hz, 1H), 7.66 (d,J=7.8 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 8.05 (s, 1H).

[0912] Step 2.

[0913] 3-Chloromethylbenzoyl azide (0.142 g, 0.726 mmol) and toluene(2.0 mL) were combined in a 10 mL round-bottom flask. The reaction flaskwas purged with N₂, equipped with magnetic stirrer, and heated to 110°C. After 2 hrs, the reaction mixture was cooled to R.T, and the3-aminobenzothiepene prepared in Step 5 of Example 1398 (0.365 g, 0.796mmol) was added. After 2.25 hrs, the mixture was heated to 50° C. After0.75 hrs, 3-chloromethylbenzoyl azide (0.025 g, 0.128 mmol) was added,and the reaction mixture was heated to reflux. After 0.5 hrs, thereaction mixture was cooled to R.T. and concentrated in vacuo.Purification by flash chromatography on silica gel eluting with 20-30%EtOAc/hexane and concentrated in vacuo gave a white foamy solid (0.309g, 62%). ¹H NMR (CDCl₃) δ 0.71 (t, J=5.4 Hz, 3H), 0.88 (t, J=6.3 Hz,3H), 1.03-1.60 (m, 11H), 1.85 (d, 6.3 Hz, 1H), 2.27 (m, 1H), 2.76 (s,6H), 3.15 (t, 2H), 4.17 (d, J=6.6 Hz, 1H), 4.48 (s, 2H), 5.42 (s, 1H),6.07 (s, 1H), 6.99 (d, J=7.5 Hz), 7.18-7.26 (m, 2H), 7.30-7.41 (m, 3H),7.63 (s, 1H), 7.86 (d, J=9.0 Hz, 2H), 7.96 (s, 1H), 8.17 (s, 1H). HRMS(M+Li). Calculated for C₃₄H₄₄N₃O₄SClLi: 632.2901. Found: 632.2889.

EXAMPLE 1437

[0914] Preparation of:

[0915] 1,4-Diazabicyclo(2.2.2)octane (0.157 g, 1.40 mmol) andacetonitrile (1.00 mL) were combined in a 10 mL round-bottom flask. Thereaction flask was purged with N₂ and equipped with magnetic stirrer. Asolution of the product of Example 1436 (0.262 g, 0.418 mmol) inacetonitrile (2.70 mL) was added. After 2.5 hrs, a white precipitate hadhad formed. Ethyl ether (6.0 mL) was added, and the precipitate wasfiltered, washed with ethyl ether, and dried in vacuo to yield a whitesolid (0.250 g, 80%). mp 246.0-248.0° C.; ¹H NMR (CD₃OD) δ 0.88 (m, 6H),1.03-1.55 (m, 10H), 1.76 (m, 1H), 2.11 (m, 1H), 2.74 (s, 6H), 3.11 (m,8H), 3.37 (m, 6H), 4.12 (s, 1H), 4.39 (s, 2H), 5.31 (s, 1H), 6.11 (s,1H), 6.52 (dd, J=8.7, 1.8 Hz, 1H), 7.09 (d, J=7.2 Hz, 1H), 7.23 (d,J=6.9 Hz, 1H), 7.32-7.38 (m, 2H), 7.47 (m, 2H), 7.58 (s, 1H), 7.73 (d,J=8.7 Hz, 2H). HRMS. Calculated for C₄₀H₅₆N₅O₄SCI: 702.4053. Found:702.4064. Anal. Calculated for C40H56N504SCl: C, 65.06; H, 7.64; N,9.48; S, 4.34; Cl, 4.80. Found: C, 64.90; H, 7.77; N, 9.42; S, 4.16; Cl,4.89.

EXAMPLES 1438 - 1454

[0916] The compounds of Examples 1438 through 1454 can be prepared inaccordance with one or more of the synthetic schemes previouslydisclosed in this application or using methods known to those skilled inthe art.

EXAMPLE 1455

[0917]

[0918] The 3-aminobenzothiepine of step 5 of Example 1398 (0.0165g/0.0360 mmol), M-NCO-5000 (0.150 g/0.30 mmol) (Methoxy-PEG-NCO, MW5000, purchased from Shearwater Polymers Inc., 2130 Memorial Parkway,SW, Huntsville, Alabama 35801), and CDCl₃ (0.7 mL) were combined in an 8mm NMR tube. The tube was purged with N₂. After 72 hrs, the reactionmixture was heated to 50° C. After 24 hrs, an additional aliquot of the3-aminobenzothiepine of step 5 of Example 1398 (0.0077 g/0.017 mmol) wasadded. After 24 hrs, the reaction mixture was transferred to a 2 mL vialand evaporated to dryness with a N₂ purge. The resulting white solid wasdissolved in hot ethyl ether (2.0 mL) and ethyl acetate (0.057 mL/4drops), cooled to precipitate and filtered. This precipitation procedurewas repeated until no starting material was detected in the precipitate(TLC: SiO₂/80% EtOAc/hexanes). Concentrated in vacuo to give a whitesolid (0.0838 g/51%). ¹H NMR (CDCl3) d 0.82-0.90 (m, 6H), 1.05-1.49 (m,14H), 1.18 (t, J=6.8 Hz, 2H), 1.59 (bt, 1H), 2.18 (bt, 1H), 2.34 (s,2H), 2.78 (s, 6H), 3.04 (ABq, 2H), 3.35-3.80 (m, 625H), 4.09 (d, J=7.2Hz, 2H), 5.42 (s, 1H), 5.78 (s, 1H), 6.04 (d, J=16 Hz, 1H), 6.47 (dd,J=6.4, 3.2 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 7.31 (bs, 1H), 7.60 (d,J=7.6 Hz, 1H), 7.66 (s, 1H), 7.85 (d, J=8.8 Hz, 1H). Mass spectroscopydata also verified desired product.

BIOLOGICAL ASSAYS

[0919] The utility of the compounds of the present invention is shown bythe following assays. These assays are performed in vitro and in animalmodels essentially using a procedure recognized to show the utility ofthe present invention.

[0920] In Vitro Assay of compounds that inhibit IBAT-mediated uptake of[¹⁴C]-Taurocholate (TC) in H14 Cells

[0921] Baby hamster kidney cells (BHK) transfected with the cDNA ofhuman IBAT (H14 cells) are seeded at 60,000 cells/well in 96 wellTop-Count tissue culture plates for assays run within in 24 hours ofseeding, 30,000 cells/well for assays run within 48 hours, and 10,000cells/well for assays run within 72 hours.

[0922] On the day of assay, the cell monolayer is gently washed oncewith 100 il assay buffer (Dulbecco's Modified Eagle's medium with 4.5g/L glucose+0.2% (w/v) fatty acid free bovine serum albumin- (FAF)BSA).To each well 50 il of a two-fold concentrate of test compound in assaybuffer is added along with 50 pl of 6 μM [¹⁴C]-taurocholate in assaybuffer (final concentration of 3 μM [L¹⁴C]-taurocholate). The cellculture plates are incubated 2 hours at 37° C. prior to gently washingeach well twice with 100 μl 4° C. Dulbecco's phosphate-buffered saline(PBS) containing 0.2% (w/v) (FAF)BSA. The wells are then gently washedonce with 100 μl 4° C. PBS without (FAF)BSA. To each 200 ol of liquidscintillation counting fluid is added, the plates are heat sealed andshaken for 30 minutes at room temperature prior to measuring the amountof radioactivity in each well on a Packard Top-Count instrument.

[0923] In Vitro Assay of compounds that inhibit uptake of [¹⁴C]-Alanine

[0924] The alanine uptake assay is performed in an identical fashion tothe taurocholate assay, with the exception that labeled alanine issubstituted for the labeled taurocholate.

[0925] In Vivo Assay of compounds that inhibit Rat Ileal uptake of[¹⁴C]-Taurocholate into Bile

[0926] (See“Metabolism of 3α,7β-dihydroxy-7α-methyl-5β-cholanoic acidand 3α,7β-dihydroxy-7α-methyl-5β-cholanoic acid in hamsters” inBiochimica et Biophysica Acta 833 (1985) 196-202 by Une et al.)

[0927] Male wistar rats (200-300 g) are anesthetized with inactin @100mg/kg. Bile ducts are cannulated with a 10″ length of PE10 tubing. Thesmall intestine is exposed and laid out on a gauze pad. A canulae (⅛″luer lock, tapered female adapter) is inserted at 12 cm from thejunction of the small intestine and the cecum. A slit is cut at 4 cmfrom this same junction (utilizing a 8 cm length of ileum). 20 ml ofwarm Dulbeccols phosphate buffered saline, pH 6.5 (PBS) is used to flushout the intestine segment. The distal opening is cannulated with a 20 cmlength of silicone tubing (0.02″ I.D.×0.037″ O.D.). The proximalcannulae is hooked up to a peristaltic pump and the intestine is washedfor 20 min with warm PBS at 0.25 ml/min. Temperature of the gut segmentis monitored continuously. At the start of the experiment, 2.0 ml ofcontrol sample ([¹⁴C]-taurocholate @ 0.05 mi/ml with 5 mM coldtaurocholate) is loaded into the gut segment with a 3 ml syringe andbile sample collection is begun. Control sample is infused at a rate of0.25 ml/min for 21 min. Bile samples fractions are collected every 3minute for the first 27 minutes of the procedure. After the 21 min ofsample infusion, the ileal loop is washed out with 20 ml of warm PBS(using a 30 ml syringe), and then the loop is washed out for 21 min withwarm PBS at 0.25 ml/min. A second perfusion is initiated as describedabove but this with test compound being administered as well (21 minadministration followed by 21 min of wash out) and bile sampled every 3min for the first 27 min. If necessary, a third perfusion is performedas above that typically contains the control sample.

[0928] Measurement of Hepatic Cholesterol Concentration (HEPATIC CHOL)

[0929] Liver tissue was weighed and homogenized in chloroform:methanol(2:1). After homogenization and centrifugation the supernatant wasseparated and dried under nitrogen. The residue was dissolved inisopropanol and the cholesterol content was measured enzymatically,using a combination of cholesterol oxidase and peroxidase, as describedby Allain, C. A., et al. (1974) Clin. Chem. 20, 470.

[0930] Measurement of Hepatic HMG CoA-Reductase Activity (HMG COA)

[0931] Hepatic microsomes were prepared by homogenizing liver samples ina phosphate/sucrose buffer, followed by centrifugal separation. Thefinal pelleted material was resuspended in buffer and an aliquot wasassayed for HMG CoA reductase activity by incubating for 60 minutes at37° C. in the presence of ¹⁴C-HMG-CoA (Dupont-NEN). The reaction wasstopped by adding 6N HCl followed by centrifugation. An aliquot of thesupernatant was separated, by thin-layer chromatography, and the spotcorresponding to the enzyme product was scraped off the plate, extractedand radioactivity was determined by scintillation counting. (Reference:Akerlund, J. and Bjorkhem, I. (1990) J. Lipid Res. 31, 2159).

[0932] Determination of Serum Cholesterol (SER.CHOL, HDL-CHOL, TGI andVLDL+LDL)

[0933] Total serum cholesterol (SER.CHOL) was measured enzymaticallyusing a commercial kit from Wako Fine Chemicals (Richmond, Va.);Cholesterol C11, Catalog No. 276-64909. HDL cholesterol (HDL-CHOL) wasassayed using this same kit after precipitation of VLDL and LDL withSigma Chemical Co. HDL Cholesterol reagent, Catalog No. 352-3 (dextransulfate method). Total serum triglycerides (blanked) (TGI) were assayedenzymatically with Sigma Chemical Co. GPO-Trinder, Catalog No. 337-B.VLDL and LDL (VLDL+LDL) cholesterol concentrations were calculated asthe difference between total and HDL cholesterol.

[0934] Measurement of Hepatic Cholesterol 7-α-Hydroxylase Activity(7a-OHase)

[0935] Hepatic microsomes were prepared by homogenizing liver samples ina phosphate/sucrose buffer, followed by centrifugal separation. Thefinal pelleted material was resuspended in buffer and an aliquot wasassayed for cholesterol 7-α-hydroxylase activity by incubating for 5minutes at 37° C. in the presence of NADPH. Following extraction intopetroleum ether, the organic solvent was evaporated and the residue wasdissolved in acetonitrile/ methanol. The enzymatic product was separatedby injecting an aliquot of the extract onto a C₁₈ reversed phase HPLCcolumn and quantitating the eluted material using UV detection at 240nm. (Reference: Horton, J. D., et al. (1994) J. Clin. Invest. 93, 2084).

[0936] Rat Gavage Assay

[0937] Male Wister rats (275-300 g) are administered IBAT inhibitorsusing an oral gavage procedure. Drug or vehicle (0.2% Tween 80 in water)is administered once a day (9:00-10:0 a.m.) for 4 days at varyingdosages in a final volume of 2 mL per kilogram of body weight. Totalfecal samples are collected during the final 48 hours of the treatmentperiod and analyzed for bile acid content using an enzymatic assay asdescribed below. Compound efficacy is determined by comparison of theincrease in fecal bile acid (FBA) concentration in treated rats to themean FBA concentration of rats in the vehicle group.

[0938] Measurement of Fecal Bile Acid Concentration (PBA)

[0939] Total fecal output from individually housed hamsters wascollected for 24 or 48 hours, dried under a stream of nitrogen,pulverized and weighed. Approximately 0.1 gram was weighed out andextracted into an organic solvent (butanol/water). Following separationand drying, the residue was dissolved in methanol and the amount of bileacid present was measured enzymatically using the 3α-hydroxysteroidsteroid dehydrogenase reaction with bile acids to reduce NAD.(Reference: Mashige, F., et al. (1981) Clin. Chem. 27, 1352).

[0940] [³H]taurocholate Uptake in Rabbit Brush Border Membrane Vesicles(BBMV)

[0941] Rabbit Ileal brush border membranes were prepared from frozenileal mucosa by the calcium precipitation method describe by Malathi etal. (Reference: (1979) Biochimica Biophysica Acta, 554, 259). The methodfor at measuring taurocholate was essentially as described by Kramer etal. (Reference: (1992) Biochimica Biophysica Acta, 1111, 93) except theassay volume was 200 μl instead of 100 μl. Briefly, at room temperaturea 190 ul solution containing 2uM [³H]-taurocholate(0.75 μCi), 20 mMtris, 100 mM NaCl, 100 mM mannitol pH 7.4 was incubated for 5 sec with10 μl of brush border membrane vesicles (60-120 μg protein). Theincubation was initiated by the addition of the BBMV while vortexing andthe reaction was stopped by the addition of 5 ml of ice cold buffer (20mM Hepes-tris, 150 mM KCl) followed immediately by filtration through anylon filter (0.2 um pore) and an additional 5 ml wash with stop buffer.

[0942] Acyl-CoA;cholesterol Acyl Transferase (ACAT)

[0943] Hamster liver and rat intestinal microsomes were prepared fromtissue as described previously (Reference: (1980) J. Biol. Chem. 255,9098) and used as a source of ACAT enzyme. The assay consisted of a 2.0ml incubation containing 24 uM Oleoyl-CoA (0.05 pCi) in a 50 mM sodiumphosphate, 2 mM DTT ph 7.4 buffer containing 0.25% BSA and 200 pg ofmicrosomal protein. The assay was initiated by the addition ofoleoyl-CoA. The reaction went for 5 min at 37° C. and was terminated bythe addition of 8.0 ml of chloroform/methanol (2:1). To the extractionwas added 125 μg of cholesterol oleate in chloroform methanol to act asa carrier and the organic and aqueous phases of the extraction wereseparated by centrifugation after thorough vortexing. The chloroformphase was taken to dryness and then spotted on a silica gel 60 TLC plateand developed in hexane/ethyl ether (9:1). The amount of cholesterolester formed was determined by measuring the amount of radioactivityincorporated into the cholesterol oleate spot on the TLC plate with aPackard instaimager.

[0944] Data from each of the noted compounds in the assays describedabove is as set forth in TABLES 5, 6, 7, and 8 as follows: TABLE 5 Invitro % % Inhibition Inhibition of TC of Alanine % of Control IC50Uptake @ Uptake @ Transport of TC in COMPOUND uM* 100 uM # 100 uM # RatIleum @ 0.1 mM # Benzothiaze 2 0 45.4 +/− 0.7 pine= 12 25 3 0 4a 3 5a 345b 40 0 72.9 ± 5.4 @ 0.5 mM 4b 9 18 6 14b 18 14a 13 13 23 15 60 19a 019b 15 8a 41 Mixture of 69 8a and 8b Mixture of 6 9a and 9b 6a 5 6b 859a 5 0% @ 25 μM 53.7 +/− 3.9 Mixture of 13 6a and 20 Mixture of 0.8 14%@ 25 μM 6d and 10a 21a 37 21c 52 21b 45 6c 2 58.5 68.8 +/− 5.7 at 0.4 nM6d 0.6 77.7 16.1 +/− 1.1 @ 0.5 mN 30.2 +/− 0.9 @ 0.15 mM 17 10 7 50 49.310a 7 77.6 62.4 =/− 2.5 @ 0.2 mM l0b 15 68.6 25 0.1 4% @ 10 μM 26.0 +/−3.3 26 2 31% @ 25 μM 87.9 +/−1.5 27 5 7% @ 20 μM 28 8 31% @ 20 μM 29 88@ 50 μM 30 96 @ 50 μM 31 41 @ 50 μM 37 3 0% @ 5 μM 38 0.3 11% @ 5 μM20.6 +/− 5.7 40 49 @ 50 μM 41 2 0% @ 20 μM 42 1.5 43 1.5 16% @ 25 μM 482 22% @ 20 μM 49 0.15 21% @ 200 μM 21.2 +/− 2.7 57 51 @ 50 μM 58 20 @ 50μM 59 70 60 9 59 61 30 175 62 10 63 90 @ 6 μM 64 l00 @ 6 μM

[0945] TABLE 6 Compound TC-uptake TC-uptake TC-uptake ACAT ACAT (H14Ileal (BBMV) (liver) intestine cells) Loop IC(50) EC(50) IC(50) IC(50)IC(50) COMP.   1 μM 74 μM   3 μM 20 μM 20 μM EXAMPLE* 6d 0.6 μM 31 μM1.5 μM 25 μM 20 μM *38  0.3 μM 12 μM   2 μM 25 μM N.D. 49 0.1 μM 12 μMN.D.  6 μM N.D. 25 0.1 μM 20 μM 0.8 μM  8 μM  8 μM

[0946] TABLE 7 EFFICACY OF COMPOUND NO. 25 IN CHOLESTEROL-FED HAMSTERS4% CHOLES- 0.2% PARAMETER CONTROL TYRAMINE CPD. NO. 25 WEIGHT (G) (mean± SEM, *p<0.05, A-Student's t, B-Dunnett's) day 1 117 (2) 114 (6) 117(5) day 14 127 (3) 127 (3) 132 (4) LIVER WEIGHT (G) 5.4( 0.3) 4.9 (0.4)5.8 (0.2) SER.CHOL(mg%) 143 (7) 119 (4)*A,B 126 (2)*A,B HDL-CHOL(mg%) 89(4) 76 (3)*A,B 76 (1)*A,B VLDL + LDL 54 (7) 42 (3)*A 50 (3) TGI(mg %)203 (32) 190 (15) 175 (11) HEPATIC CHOL(mg/g) 2.5 (0.3) 1.9 (0.1)*A,B1.9 (0.1)*A,B HMG COA (pm/mg/min.) 15.8 (7.6) 448.8 (21.6)*A,B 312.9(37.5)*A,B 7a-OHase (pm/mg/min.) 235.3 (25.1) 24 HR. FECAL Wt (G) 357.2(28.3)* 291.0 (6.0)*A FBA (mM/24 H/100 g) 2.3 (0.1) A,B 2.4 (0.04) 6.2(0.8) 2.7 (0.1)*A,B 11.9 (0.5)*A,B 12.3 (1.5) *A,B

[0947] TABLE 8 EFFICACY OF COMPOUND NO. 25 IN RAT ALZET MINIPUMP MODEL20 MPL/DAY PARAMETER CONTROL CPD. NO. 25 (mean ± SEM, *p<0.05, WEIGHT(G) A-Student's t, B-Dunnett's) day 1 307 (4) 307 (3) day 8 330 (4) 310(4)*A,B LIVER WEIGHT (G) 15.5 (0.6) 14.6 (0.4) SER.CHOL(mg%) 85 (3) 84(3) HEPATIC CHOL(mg/g) 21 (0.03) 2.0 (0.03) HMG COA pm/mg/min 75.1 (6.4)318.0 (40.7)*A,B 7a-OHase (pm/mg/min) 281.9 (13.9) 535.2 (35.7)*A,B 24HR. FECAL WT (G) 5.8 (0.1) 5.7 (0.4) FBA (mM/24H/100g) 17.9 (0.9) 39.1(4.5)*A,B

[0948] TABLE 9 Biological Data for Some Compounds of the PresentInvention Alanine Uptake Human TC Percent Compound IC₅₀ InhibitionNumber (μM) @ μM 101 0 @ 1.0 1U2 0.083 103 13 @ 0.25 104 0.0056 105 0.6106 0.8 107 14.0 @ 0.063 108 0.3 109 2.0 @ 0.063 110 0.09 111 2.5 1123.0 113 0.1 114 0.19 115 8.0 116 0.3 117 12.0 @ 0.625 118 0.4 119 1.3120 34.0 @ 5.0 121 0.068 122 1.07 123 1.67 124 14.0 @ 6.25 125 18.0 12618 @ 1.25 127 0.55 128 0.7 129 0.035 131 1.28 132 5.4 @ 0.063 133 16.0134 0.3 135 22.0 136 0.09 137 2.4 138 3.0 139 >25.0 140 141 142 0.5 1430.03 144 0.053 262 0.07 263 0.7 264 0.2 265 2.0 266 0.5 267 0.073 2680.029 269 0.08 270 0.12 271 0.07 272 0.7 273 1.9 274 0.18 275 5.0 @ 0.25276 0.23 277 0.04 278 3.0 279 0.4 280 0.18 281 0.019 282 0.021 283 0.35284 0.08 285 286 19.0 287 4.0 288 10.0 @ 6.25 289 0.23 290 0.054 291 0.6292 0.046 293 1.9 294 0.013 295 1.3 296 1.6 1000 1001 1002 1003 10041005 0.0004 1006 0.001 1007 0.001 1008 0.001 1009 0.001 1010 0.001 10110.001 1012 0.0015 1013 0.002 1014 0.002 1015 0.002 1016 0.002 1017 0.0021018 0.002 1019 0.002 1020 0.002 1021 0.002 1022 0.002 1023 0.002 10240.002 1025 0.002 1026 0.002 1027 0.002 1028 0.002 1029 0.002 1030 0.0021031 0.002 1032 0.002 1033 0.002 1034 0.002 1035 0.002 1036 0.002 10370.0022 1038 0.0025 1039 0.0026 1040 0.003 1041 0.003 1042 0.003 10430.003 1044 0.003 1045 0.003 1046 0.003 1047 0.003 1048 0.003 1049 0.0031050 0.003 1051 0.003 1052 0.003 1053 0.003 1054 0.003 1055 0.003 10560.003 1057 0.003 1058 0.003 1059 0.003 1060 0.0036 1061 0.004 1062 0.0041063 0.004 1064 0.004 1065 0.004 1066 0.004 1067 0.004 1068 0.004 10690.004 1070 0.004 1071 0.004 1072 0.004 1073 0.004 1074 0.004 1075 0.00431076 0.0045 1077 0.0045 1078 0.0045 1079 0.005 1080 0.005 1081 0.0051082 0.005 1083 0.005 1084 0.005 1085 0.005 1086 0.005 1087 0.005 10880.0055 1089 0.0057 1090 0.006 1091 0.006 1092 0.006 1093 0.006 10940.006 1095 0.006 1096 0.006 1097 0.006 1098 0.006 1099 0.0063 11000.0068 1101 0.007 1102 0.007 1103 0.007 1104 0.007 1105 0.007 11060.0073 1107 0.0075 1108 0.0075 1109 0.008 1110 0.008 1111 0.008 11120.008 1113 0.009 1114 0.009 1115 0.0098 1116 0.0093 1117 0.01 1118 0.011119 0.01 1120 0.01 1121 0.01 1122 0.011 1123 0.011 1124 0.011 11250.012 1126 0.013 1127 0.013 1128 0.017 1129 0.018 1130 0.018 1131 0.021132 0.02 1133 0.02 1134 0.02 1135 0.021 1136 0.021 1137 0.021 11380.021 1139 0.021 1140 0.023 1141 0.023 1142 0.024 1143 0.027 1144 0.0281145 0.029 1146 0.029 1147 0.029 1148 0.03 1149 0.03 1150 0.03 11510.031 1152 0.036 1153 0.037 1154 0.037 1155 0.039 1156 0.039 1157 0.041158 0.06 1159 0.06 1160 0.062 1161 0.063 1162 0.063 1163 0.09 11640.093 1165 0.11 1166 0.11 1167 0.12 1168 0.12 1169 0.12 1170 0.13 11710.14 1172 0.14 1173 0.15 1174 0.15 1175 0.17 1176 0.18 1177 0.18 11780.19 1179 0.19 1180 0.2 1181 0.22 1182 0.25 1183 0.28 1184 0.28 11850.28 1186 0.3 1187 0.32 1188 0.35 1189 0.35 1190 0.55 1191 0.65 1192 1.01193 1.6 1194 1.6 1195 1.7 1196 2.0 1197 2.2 1198 2.5 1199 4.0 1200 6.11201 8.3 1202 40.0 1203 0 @ 0.063 1204 0.05 1205 0.034 1206 0.035 12070.068 1208 0.042 1209 0 @ 0.063 1210 0.14 1211 0.28 1212 0.39 1213 1.71214 0.75 1215 0.19 1216 0.39 1217 0.32 1218 0.19 1219 0.34 1220 0.21221 0.041 1222 0.065 1223 0.28 1224 0.28 1225 0.12 1226 0.046 1227 0.251228 0.038 1229 0.049 1230 0.062 1231 0.075 1232 1.2 1233 0.15 12340.067 1235 0.045 1236 0.05 1237 0.07 1238 0.8 1239 0.035 1240 0.016 12410.047 1242 0.029 1243 0.63 1244 0.062 1245 0.32 1246 0.018 1247 0.0171248 0.33 1249 10.2 1250 0.013 1251 0.62 1252 29. 1253 0.3 1254 0.851255 0.69 1256 0.011 1257 0.1 1258 0.12 1259 16.5 1260 0.012 1261 0.0191262 0.03 1263 0.079 1264 0.21 1265 0.24 1266 0.2 1267 0.29 1268 0.0351269 0.026 1270 0.026 1271 0.011 1272 0.047 1273 0.029 1274 0.028 12750.024 1276 0.029 1277 0.018 1278 0.017 1279 0.028 1280 0.76 1281 0.0551282 0.17 1283 0.17 1284 0.011 1285 0.027 1286 0.068 1287 0.071 12880.013 1289 0.026 1290 0.017 1291 0.013 1292 0.025 1293 0.019 1294 0.0111295 0.014 1296 0.063 1297 0.029 1298 0.018 1299 0.012 1300 1.0 13010.15 1302 1.4 1303 0.26 1304 0.25 1305 0.25 1306 1.2 1307 3.1 1308 0.041309 0.24 1310 1.16 1311 3.27 1312 5.0 1313 5.0 1314 0.26 1315 1.67 13163.9 1317 21.0 1318 1319 11.0 @ 0.25 1320 1321 11.1 @ 5.0 1322 3.0 @0.0063 1323 4.0 @ 0.0063 1324 43.0 @ 0.0008 1325 1.0 @ 0.0063 1326 36.0@ 0.0008 1327 3.0 @ 0.0063 1328 68.0 @ 0.0063 1329 2.0 @ 0.0063 1330 9.0@ 0.0063 1331 57.0 @ 0.0008 1332 43.0 @ 0.0008 1333 0 @ 0.0063 1334 50.0@ 0.0008 1335 38.0 @ 0.0008 1336 45.0 @ 0.0008 1337 0 @ 0.0063 1338 1.0@ 0.25 1339 0 @ 0.063 1340 9.0 @ 0.063 1341 1.0 @ 0.063 1342 1.0 @ 0.0631343 1344 1345 13.0 @ 0.25 1346 1347 0.0036 1348 1349 1350 1351 0.441352 0.10 1353 0.0015 1354 0.006 1355 0.0015 1356 0.22 1357 0.023 13580.008 1359 0.014 1360 0.003 1361 0.004 1362 0.019 1363 0.008 1364 0.0061365 0.008 1366 0.015 1367 0.002 1368 0.005 1369 0.005 1370 0.002 13710.004 1372 0.004 1373 0.008 1374 0.007 1375 0.002 1449 0.052 1450 0.0391451 0.014

[0949] Additional in vitro taurocholate uptake tests and in vivo ratgavage tests were conducted on the 5 following compounds listed inTables 10 and 11. TABLE 10 In Vitro Taurocholate Uptake Assay Data forSome Additional Compounds of the Present Invention Compound of ExampleHuman TC IC50 Number (nM) 1402 25 1403 23 1404 10 1405 21 1406 4 1407 31408 1 1409 0.9 1410 2 1411 2 1412 3 1413 3 1414 15 1415 2 1416 14 14172 1418 <1 1419 3 1420 11 1421 4 1422 3 1423 3 1424 14 1425 2 1426 0.31427 2 1428 0.7 1429 1430 3 1431 5 1432 26 1433 67

[0950] TABLE 11 Rat Gavage Assay Data for Some Additional Compounds ofthe Present Invention Delta (micromoles Compound of Dose fecal bileExample No. Study No. (mg/kg/day) acid per day) 1402 28 5 58.2 .2 1.3.04 0.3 1402 30 2 50.3 .4 40.9 .08 48.5 .016 22.9 1403 30 2 41.6 .4 35.2.08 11.9 .016 3 1404 28 5 93.7 .2 59.1 .04 33.5 1406 32 2 47.8 .4 31.6.08 12.8 .016 −8.5 1407 32 2 51.9 .4 30.1 .08 27.5 .016 6.4 1407 33 2 35.4 12.7 .08 −.04 .016 −4.5 1408 29 2 41.2 .4 36.8 .08 16.8 .016 −3.31408 37 2 26.2 .4 45.2 .08 26.3 .016 6.6 1409 33 2 19.2 .4 28.7 .08 14.1.016 −1.7 1409 41 2 44.2 .4 35.9 .08 14.5 .016 11 1410 33 32.4 34.3 27.99.3 1410 35 2 26.2 .4 36.5 .08 18.5 .016 20.4 1411 34 2 63.4 .4 54.1 .0833 .016 22.3 1413 26 5 52.3 .2 42.4 .04 19 1414 27 5 45.2 .2 39.5 .0414.3 1414 31 2 41.5 .4 33.7 .08 29 .016 3.8 1415 28 5 59.9 .2 48.1 .0423.9 1415 37 2 48.9 .4 25.7 .08 27.1 .016 12.7 1416 29 .2 46.1 .4 21.9.08 25 .016 −7.8 1417 31 2 51.4 .4 42 .08 39.6 .016 29.3 1418 29 2 20.3.4 29.5 .08 −4.6 .016 −10 1419 31 2 28.5 .4 13.9 .08 10.3 .016 5.8 142031 2 53.1 .4 45 .08 38.1 .016 29.6 1421 32 2 57.8 .4 27.7 .08 25.3 .0164.7 1423 34 2 56.5 .4 69.3 .08 35.3 .016 14.4 1425 21 5 91.8 .2 100. .0466.4 1425 30 2 44.6 .4 62 .08 69.5 .016 31.6 1425 40 2 48.3 .4 45 .0831.2 .016 30 1426 33 2 52.4 .4 19.5 .08 23.1 .016 24.6 1426 35 2 37.7 .441.7 .08 40.5 .016 24.6 1426 39 2 54.3 .4 48.7 .08 51.8 .016 26.8 142643 2 40.8 .4 21.7 .08 5.9 .016 4.1 1427 40 2 36.7 .4 35.8 .08 27.3 .01613.8 1428 34 2 40.4 .4 64.9 .08 24.4 .016 12.2 1428 42 2 46 .4 40.7 .0826 .016 1.1 1429 41 2 34.5 .4 24.9 .08 18.7 .016 9.2 1429 42 2 47.1 .431.1 .08 35.5 .016 4.8 1430 30 2 51.2 .4 50.4 .08 20.7 .016 −5.6 1431 3228.3 45.8 21.9 1.1 1432 28 5 36.2 .2 9.7 .04 2.4 1433 24 20 66.5 2 47.4.2 26.5

[0951] The examples herein can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

[0952] Novel compositions of the invention are further illustrated inattached Exhibits A and B.

[0953] The invention being thus described, it is apparent that the samecan be varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the present invention, and allsuch modifications and equivalents as would be obvious to one skilled inthe art are intended to be included within the scope of the followingclaims.

Exhibit A

[0954] TABLE C2 Alternative Compounds #2 (Families F101-F123)

Cpd Family # R¹═R² R⁵ (R^(x))q F101 CHOSEN Ph— CHOSEN FROM FROM TABLE 1TABLE 1 F102 CHOSEN p-F—Ph— CHOSEN FROM FROM TABLE 1 TABLE 1 F103 CHOSENm-F—Ph— CHOSEN FROM FROM TABLE 1 TABLE 1 F104 CHOSEN p-CH₃O—Ph— CHOSENFROM FROM TABLE 1 TABLE 1 F105 CHOSEN m-CH₃O—Ph— CHOSEN FROM FROM TABLE1 TABLE 1 F106 CHOSEN p-(CH₃)₂N—Ph— CHOSEN FROM FROM TABLE 1 TABLE 1F107 CHOSEN m-(CH₃)₂N—Ph CHOSEN FROM FROM TABLE 1 TABLE 1 F108 CHOSENI⁻, p-(CH₃)₃—N⁺—Ph— CHOSEN FROM FROM TABLE 1 TABLE 1 F109 CHOSEN I⁻,m-(CH₃)₃—N⁺—Ph— CHOSEN FROM FROM TABLE 1 TABLE 1 F110 CHOSEN I⁻,p-(CH₃)₃—N⁺—CH₂CH₂— CHOSEN FROM (OCH₂CH₂)₂—O—Ph— FROM TABLE 1 TABLE 1F111 CHOSEN I⁻, m-(CH₃)₃—N⁺—CH₂CH₂— CHOSEN FROM (OCH₂CH₂)₂—O—Ph— FROMTABLE 1 TABLE 1 F112 CHOSEN I⁻, p-(N,N- CHOSEN FROMdimethylpiperazine)-(N′)— FROM TABLE 1 CH₂—(OCH₂CH₂)₂—O—Ph TABLE 1 F113CHOSEN I⁻, m-(N,N- CHOSEN FROM dimethylpiperazine)-(N′)— FROM TABLE 1CH₂—(OCH₂CH₂)₂—O—Ph— TABLE 1 F114 CHOSEN m-F—Ph— CHOSEN FROM p-CH₃O—FROM TABLE 1 TABLE 1 F115 CHOSEN 3,4,dioxy-methylene-Ph CHOSEN FROM FROMTABLE 1 TABLE 1 F116 CHOSEN m-F—Ph— CHOSEN FROM p-F—Ph— FROM TABLE 1TABLE 1 F117 CHOSEN m-CH₃O— CHOSEN FROM p-F—Ph— FROM TABLE 1 TABLE 1F118 CHOSEN 4-pyridine CHOSEN FROM FROM TABLE 1 TABLE 1 F119 CHOSENN-methyl-4-pyridinium CHOSEN FROM FROM TABLE 1 TABLE 1 F120 CHOSEN3-pyridine CHOSEN FROM FROM TABLE 1 TABLE 1 F121 CHOSENN-methyl-3-pyridinium CHOSEN FROM FROM TABLE 1 TABLE 1 F122 CHOSEN2-pyridine CHOSEN FROM FROM TABLE 1 TABLE 1 F123 CHOSEN p-CH₃O₂C—Ph—CHOSEN FROM FROM TABLE 1 TABLE 1

[0955]

What is claimed is:
 1. A compound of formula (I):

wherein: q is an integer from 1 to 4; n is an integer from 0 to 2; R¹and R² are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl,alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R²A⁻, SR⁹, S⁺R⁹R¹⁰A⁻. P⁺R⁹R¹⁰R¹¹A⁻,S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, whereinalkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl,(polyalkyl)aryl, and cycloalkyl optionally have one or more carbonsreplaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻, P⁺R⁹R¹⁰A⁻, orphenylene, wherein R⁹, R¹⁰, and R^(w) are independently selected fromthe group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,acyl, heterocycle, ammoniumalkyl, arylalkyl, and alkylammoniumalkyl; orR¹ and R² taken together with the carbon to which they are attached formC₃-C₁₀ cycloalkyl; R³ and R⁴ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle,OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein R⁹ and R¹⁰ are asdefined above; or R³ and R⁴ together form ═O, ═NOR¹¹, ═S, ═NNR¹¹R¹²,═NR⁹, or ═CR¹¹R¹² ₁₂, wherein R¹¹ and R¹² are independently selectedfrom the group consisting of H, alkyl, alkenyl, alkynyl, aryl,arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl,carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹,SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, wherein R⁹ and R¹⁰are as defined above, provided that both R³ and R⁴ cannot be OH, NH₂,and SH, or R¹¹ and R¹² together with the nitrogen or carbon atom towhich they are attached form a cyclic ring; R⁵ and R⁶ are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocycle, quaternary heterocycle, OR⁹, SR⁹, S(O)R⁹,SO₂R⁹, and SO₃R⁹, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycle, quaternary heterocycle, and quaternary heteroaryl can besubstituted with one or more substituent groups independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, polyalkyl,polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl,quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR¹³,NR¹³R¹⁴ SR¹³ S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, CR¹³, P⁺R⁷R⁸A-,or phenylene, and R¹³, R¹⁴, and R¹⁵ are independently selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl,arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle,quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl,alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally haveone or more carbons replaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻,PR⁹, P⁺R⁹R¹⁰A-, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, orpolypeptide, and R¹³, R¹⁴, and R¹⁵ are optionally substituted with oneor more groups selected from the groupconsisting of sulfoalkyl,quaternary heterocycle, quaternary heteroaryl, OR⁹, NR⁹R¹⁰,N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen,CONR⁹R¹⁰, SO2OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A-, S⁺R⁹R¹⁰A-, andC(O)OM, wherein R¹⁶ and R¹⁷ are independently selected from thesubstituents constituting R⁹ and M; or R¹⁴ and R¹⁵, together with thenitrogen atom to which they are attached, form a cyclic ring; and R³⁰ isselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl,and arylalkyl; and R⁷ and R⁸ are independently selected from the groupconsisting of hydrogen and alkyl; and one or more R_(x) areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl,cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle,quaternary heteroaryl, OR¹³ NR¹³R¹⁴, SR¹³, S(O)R¹³, S(O)₂R¹³, SO₃R¹³,S⁺R¹³R¹⁴A-, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM,SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴, NR14C(O)R13, C(O)OM, COR¹³, OR¹⁸,S(O)_(n)NR¹⁸, NR¹³R¹⁸, NR¹⁸OR¹⁴, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, amino acid,peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl,polyether, quaternary heterocycle, and quaternary heteroaryl can befurther substituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R²A⁻, SR⁹, S(O)R⁹, SO₂R⁹,SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰,PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein R¹⁸ isselected from the group consisting of acyl, arylalkoxycarbonyl,arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl,arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,quaternary heterocycle, and quaternary heteroaryl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo,CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, andC(O)OM, wherein in R^(x), one or more carbons are optionally replaced byO, NR¹³, N⁺R¹³R¹⁴A-, S, SO, SO₂, S⁺R¹³A⁻, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A-,phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, orpolyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide,polypeptide, and carbohydrate, one or more carbons are optionallyreplaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A-, PR⁹, P⁺R⁹R¹⁰A-, orP(O)R⁹; wherein quaternary heterocycle and quaternary heteroaryl areoptionally substituted with one or more groups selected from the groupconsisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo OR¹³,NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³,P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,provided that both R⁵ and R⁶ cannot be hydrogen or SH; provided thatwhen R⁵ or R⁶ is phenyl, only one of R¹ or R² is H; provided that whenq=1 and R^(x) is styryl, anilido, or anilinocarbonyl, only one of R⁵ orR⁶ is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrugthereof.
 2. A compound of claim 1, wherein R⁵ and R⁶ are independentlyselected from the group consisting of H, aryl, heterocycle, quaternaryheterocycle, and quaternary heteroaryl, wherein said aryl, heteroaryl,quaternary heterocycle, and quaternary heteroaryl can be substitutedwith one or more substituent groups independently selected from thegroup consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³,NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³,P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N^(+R)⁹R¹¹R¹²A⁻, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one ormore carbons replaced by O, NR⁷, N⁺R⁷R⁸A⁻, S, SO, SO₂, S⁺R⁷A⁻, PR⁷,P(O)R⁷, P⁺R⁷R⁸A⁻, or phenylene, wherein said alkyl, alkenyl, alkynyl,polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle canbe further substituted with one or more substituent groups selected fromthe group consisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷,CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl,P(O)R⁷R⁸, P⁺R⁷R⁸A⁻, and P(O)(OR⁷)OR⁸.
 3. A compound of claim 2, whereinR⁵ or R⁶ has the formula —Ar—(R^(y))_(t) wherein: t is an integer from 0to 5; Ar is selected from the group consisting of phenyl, thiophenyl,pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl,anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl,isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl,and benzoisothiazolyl; and one or more R^(y) are independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, polyalkyl,polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen,oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴,NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴,C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, andN⁺R⁹R¹¹R¹²A⁻, wherein said alkyl, alkenyl, alkynyl, polyalkyl,polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be furthersubstituted with one or more substituent groups selected from the groupconsisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo,CONR⁷R⁸, N⁺R⁷R⁸R⁹A⁻, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl,P(O)R⁷R⁸, P⁺R⁷R⁸A⁻, and P(O) (OR⁷)OR⁸, and wherein said alkyl, alkenyl,alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, andheterocycle can optionally have one or more carbons replaced by O, NR⁷,N⁺R⁷R⁸A⁻, S, SO, SO₂, S⁺R⁷A-, PR⁷, P(O)R⁷, P⁺R⁷R⁸A⁻, or phenylene.
 4. Acompound of claim 3, wherein R⁵ or R⁶ has the formula (II)


5. A compound of claim 4, wherein n is 1 or
 2. 6. A compound of claim 5,wherein one of R⁷ or R⁸ is H and the other of R⁷ or R⁸ is alkyl.
 7. Acompound of claim 5, wherein both R⁷ and R⁸ are H.
 8. A compound ofclaim 7, wherein R¹ and R² are independently selected from the groupconsisting of H and alkyl.
 9. A compound of claim 8, wherein said alkylis a C₁-C₁₀ alkyl.
 10. A compound of claim 8, wherein R and R² are bothalkyl.
 11. A compound of claim 10, wherein said alkyl is a C₁-C₁₀ alkyl.12. A compound of claim 11, wherein said alkyl is a C₂-C₇ alkyl.
 13. Acompound of claim 12, wherein said alkyl is a C₂-C₄ alkyl.
 14. Acompound of claim 13, wherein said alkyl is independently selected fromthe group consisting of ethyl, n-propyl, n-butyl, and isobutyl.
 15. Acompound of claim 8, wherein R¹ and R² are each n-butyl.
 16. A compoundof claim 8, wherein one of R¹ and R² is ethyl and the other of R¹ and R²is n-butyl.
 17. A compound of claim 15, wherein q is 1, 2, or
 3. 18. Acompound of claim 16, wherein q is 1, 2, or
 3. 19. A compound of claim17, wherein q is 1 or
 2. 20. A compound of claim 19, wherein q is
 1. 21.A compound of claim 18, wherein q is 1 or
 2. 22. A compound of claim 21,wherein q is
 1. 23. A compound of claim 19, wherein R³ and R⁴ areindependently selected from the group consisting of H and OR⁹.
 24. Acompound of claim 21, wherein R³ and R⁴ are independently selected fromthe group consisting of H and OR⁹.
 25. A compound of claim 23, whereinR⁹ is H.
 26. A compound of claim 24, wherein R⁹ is H.
 27. A compound ofclaim 25, wherein one or more R^(x) are in the 7-, 8-, or 9-position ofthe benzo ring of formula (I).
 28. A compound of claim 26, wherein saidR^(x) is in the 7-, 8-, or 9- position of the benzo ring of formula 29.A compound of claim 27, wherein said R^(x) are in the 7- and 9-positions of the benzo ring of formula (I).
 30. A compound of claim 28,wherein said R^(x) is in the 7-position of the benzo ring of formula(I).
 31. A compound of claim 29, wherein said one or more R^(x) areindependently selected from the group consisting of alkyl, aryl,cycloalkyl, heterocycle, polyalkyl, acyloxy, polyether, halogen, OR¹³,NR¹³R¹⁴, NR¹³NR¹⁴R¹⁵, N⁺R⁹R¹¹R¹²A⁻, SR¹³, S⁺R¹³R¹⁴, CO₂R¹³, NR¹⁴C(O)R¹³,and NR¹⁴C(O)R¹³, wherein alkyl, aryl, cycloalkyl, heterocycle,polyalkyl, acyloxy, and polyether, can be further substituted with OR⁹,NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN,halogen, CONR⁹R¹⁰ SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶ )OR¹⁷, P⁺R⁹R¹¹R¹²A⁻,S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein in R^(x), one or more carbons areoptionally replaced by O, NR¹³, N⁺R¹³R¹⁴A⁻, S, SO, SO₂, S⁺R⁹R¹⁰A⁻, PR¹³,P(O)R¹³, P⁺R⁹R¹⁰A⁻, phenylene, amino acid, peptide, polypeptide,carbohydrate, polyether, or polyalkyl, and wherein in said polyalkyl,phenylene, amino acid, peptide, polypeptide, and carbohydrate, one ormore carbons are optionally replaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂,S⁺R⁹A-, PR⁹, P⁺R⁹R¹⁰A-, or P(O)R⁹.
 32. A compound of claim 30, whereinsaid R^(x) is selected from the group consisting of alkyl, aryl,cycloalkyl, heterocycle, polyalkyl, acyloxy, polyether, halogen, OR¹³,NR¹³R¹⁴, NR¹³NR¹⁴R¹⁵, N⁺R⁹R¹¹R¹²A⁻, SR¹³, S⁺R¹³R¹⁴, CO₂R¹³, NR¹⁴C(O)R¹³,and NR¹⁴C(O)R¹³, wherein alkyl, aryl, cycloalkyl, heterocycle,polyalkyl, acyloxy, and polyether, can be further substituted with OR⁹,NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN,halogen, CONR⁹R¹⁰ SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻,S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein in R^(x), one or more carbons areoptionally replaced by O, NR¹³, N⁺R¹³R¹⁴A-, S, SO, SO₂, S⁺R¹³A-, PR¹³,P(O)R¹³, P⁺R¹³R¹⁴A-, phenylene, amino acid, peptide, polypeptide,carbohydrate, polyether, or polyalkyl, and wherein in said polyalkyl,phenylene, amino acid, peptide, polypeptide, and carbohydrate, one ormore carbons are optionally replaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂,S⁺R⁹A-, PR⁹, P⁺R⁹R¹⁰A-, or P(O)R⁹.
 33. A compound of claim 31, whereinsaid one or more R^(x) are independently selected from the groupconsisting of polyether, OR¹³, NR¹³R¹⁴, and N⁺R⁹R¹¹R¹²A⁻.
 34. A compoundof the claim 32, wherein said R^(x) is selected from the groupconsisting of polyether, OR¹³, NR¹³R¹⁴, and N⁺R⁹R¹¹R¹²A⁻.
 35. A compoundof claim 33, wherein said one or more Rx are independently selected fromthe group consisting of OR¹³ and NR¹³R¹⁴.
 36. A compound of claim 34,wherein said R^(x) is independently selected from the group consistingof OR¹³ and NR¹³R¹⁴.
 37. A compound of claim 35, wherein R¹³ and R¹⁴each methyl.
 38. A compound of the claim 36, wherein R¹³ and R¹⁴ eachmethyl.
 39. A compound of claim 31, wherein one or more R^(y) areindependently in the 3- or the 4-position of the phenyl ring of formula(II).
 40. A compound of claim 32, wherein one or more Ry areindependently in the 3- or the 4- position of the phenyl ring of formula(II).
 41. A compound of claim 39, wherein t is 1 or
 2. 42. A compound ofclaim 40, wherein t is 1 or
 2. 43. A compound of claim 41, wherein saidone or more R are independently selected from the group consisting ofalkyl, polyether, fluoride, chloride, bromide, iodide, NR¹³R¹⁴,NR¹⁴(O)R¹³, and OR¹³, wherein alkyl and polyether can be furthersubstituted with SO₃R⁹, N⁺R⁹R¹¹R¹²A⁻, and quaternary heteroaryl.
 44. Acompound of claim 42, wherein said R^(y) is independently selected fromthe group consisting of alkyl, polyether, fluoride, chloride, bromide,iodide, NR¹³R¹⁴, NR¹⁴C(O)R¹³, and OR¹³, wherein alkyl and polyether canbe further substituted with SO₃R⁹, NR⁺R⁹R¹¹R¹²A⁻, and quaternaryheteroaryl.
 45. A compound of claim 43, wherein said one or more R^(y)are independently selected from the group consisting of alkyl,polyether, fluoride, NR¹³R¹⁴, NR¹⁴C(O)R¹³, and OR¹³, wherein alkyl andpolyether can be further substituted with SO₃R⁹, N⁺R⁹R¹¹R¹²A⁻, andquaternary heteroaryl.
 46. A compound of claim 44 wherein said R^(y) isindependently selected from the group consisting of alkyl, polyether,fluoride, NR¹³R¹⁴, NR¹⁴C(O)R¹³, and OR¹³, wherein alkyl and polyethercan be further substituted with SO₃R⁹, N⁺R⁹R¹¹R¹²A⁻, and quaternaryheteroaryl.
 47. A compound of claim 45, wherein said R¹³ and R¹⁴ arealkyl, wherein alkyl can be further substituted with SO³R⁹,N⁺R⁹R¹¹R¹²A⁻, and quaternary heteroaryl.
 48. A compound of claim 46,wherein said R⁹ and R¹⁰ are alkyl, wherein alkyl can be furthersubstituted with SO³R⁹, N⁺R⁹R¹¹R¹²A⁻, and quaternary heteroaryl.
 49. Acompound of claim 47, wherein n is
 2. 50. A compound of claim 48,wherein n is
 2. 51. A compound of claim 49, wherein said OH group is ina syn relationship to said structure of formula (II).
 52. A compound ofclaim 50, wherein said OH group is in a syn relationship to saidstructure of formula (II).
 53. A compound of claim 51, having theformula:


54. A compound of claim 51, having the formula:


55. A compound of claim 51, having the formula:


56. A compound of claim 51, having the formula:


57. A compound of claim 51, having the formula:


58. A compound of claim 52, having the formula:


59. A compound of claim 52, having the formula:


60. A compound of claim 52, having the formula:


61. A compound of claim 52, having the formula:


62. A compound of claim 52, having the formula:


63. A compound of claim 31, wherein n is
 1. 64. A compound of claim 63,wherein R^(y) is H.
 65. A compound of claim 64, having the formula


66. A compound of claim 4, wherein R¹ and R² are independently selectedfrom the group consisting of H and alkyl.
 67. A compound of claim 66,wherein said alkyl is C₁-C₁₀ alkyl.
 68. A compound of claim 67, whereinsaid alkyl is C₂-C₇ alkyl.
 69. A compound of claim 68, wherein saidalkyl is C₂-C₄ alkyl.
 70. A compound of claim 69, wherein R¹ and R² areindependently selected from the group consisting of ethyl, n-propyl,n-butyl, and isobutyl.
 71. A compound of claim 4, wherein R³ and R⁴ areindependently selected from the group consisting of H and OR⁹.
 72. Acompound of claim 71, wherein R⁹ is H.
 73. A compound of claim 4,wherein n is
 2. 74. A compound of claim 3, wherein R³ and R⁴ areindependently selected from the group consisting of H and OR⁹.
 75. Acompound of claim 74, wherein R9 is H.
 76. A compound of claim 3,wherein one of R⁷ or R⁸ is H.
 77. A compound of claim 76, wherein bothR⁷ and R⁸ are H.
 78. A compound of claim 3, wherein said one or moreR^(x) are independently selected from the group consisting of alkyl,aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, polyether, halogen,OR¹³, NR¹³R¹⁴, NR¹³NR¹⁴R¹⁵, N⁺R⁹R¹¹R¹²A⁻, SR¹³, S⁺R¹³R¹⁴, CO₂R¹³,NR¹⁴C(O)R¹³, and NR¹⁴C(O)R¹³, wherein alkyl, aryl, cycloalkyl,heterocycle, polyalkyl, acyloxy, and polyether, can be furthersubstituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹,oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(R¹⁶)R¹⁷,P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein in R^(x), one or morecarbons are optionally replaced by O, NR¹³, N⁺R¹³R¹⁴A-, S, SO, SO₂,S⁺R¹³A-, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A⁻, phenylene, amino acid, peptide,polypeptide, carbohydrate, polyether, or polyalkyl, and wherein in saidpolyalkyl, phenylene, amino acid, peptide, polypeptide, andcarbohydrate, one or more carbons are optionally replaced by O, NR⁹,N⁺R⁹R¹¹A⁻, S, SO, SO₂, S⁺R⁹A⁻, PR⁹, P⁺R⁹R¹⁰A⁻, or P(O)R⁹.
 79. A compoundof claim 78, wherein said one or more R^(x) are independently selectedfrom the group consisting of polyether, OR¹³, NR¹³R¹⁴, and N⁺R⁹R¹¹R¹²A⁻.80. A compound of claim 79, wherein said one or more R^(x) areindependently selected from the group consisting of OR¹³ and NR¹³R¹⁴.81. A compound of claim 80, wherein R¹³ and R¹⁴ are each methyl.
 82. Acompound of claim 3, wherein one or more R^(y) are independently in the3- or the 4-position of the phenyl ring of formula (II).
 83. A compoundof claim 82, wherein one or more R^(y) is selected from the groupconsisting of alkyl, polyether, fluoride, chloride, bromide, iodide,NR⁹R¹⁰, and NC(O)R⁹, wherein alkyl and polyether can be substituted withSO₃R⁹, N⁺R⁹R¹¹R¹²A⁻, and quaternary heteroaryl.
 84. A compound of claim83, wherein R⁹ and R¹⁰ are alkyl.
 85. A compound of claim 84, whereinone or more R^(y) is selected from the group consisting of alkyl,polyether, fluoride, chloride, bromide, iodide, NR⁹R¹⁰, and NC(O)R⁹. 86.A compound of claim 1, wherein said one or more R^(x) are independentlyselected from the group consisting of alkyl, aryl, cycloalkyl,heterocycle, polyalkyl, acyloxy, polyether, halogen, OR¹³, NR¹³R¹⁴,NR¹³NR¹⁴R¹⁵, N⁺R⁹R¹¹R¹²A⁻, SR¹³, S⁺R¹³R¹⁴, CO₂R¹³, NR¹⁴C(O)R¹³, andNR¹⁴(O)R¹³, wherein alkyl, aryl, cycloalkyl, heterocycle, polyalkyl,acyloxy, and polyether, can be further substituted with OR⁹, NR⁹R¹⁰,NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN,halogen, CONR⁹R¹⁰ SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻,S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein in R^(x), one or more carbons areoptionally replaced by O, NR¹³, N⁺R¹³R¹⁴A⁻, S, SO, SO₂, S⁺R¹³A-, PR¹³,P(O)R¹³, P⁺R¹³R¹⁴A-, phenylene, amino acid, peptide, polypeptide,carbohydrate, polyether, or polyalkyl, and wherein in said polyalkyl,phenylene, amino acid, peptide, polypeptide, and carbohydrate, one ormore carbons are optionally replaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂,S⁺R⁹A-, PR⁹, P⁺R⁹R¹⁰A-, or P(O)R⁹.
 87. A compound of claim 1, wherein nis 1 or
 2. 88. A compound of claim 87, wherein n is
 2. 89. A compound ofclaim 1, wherein R¹ and R² are independently selected from the groupconsisting of H and alkyl.
 90. A compound of claim 89, wherein saidalkyl is C₁-C₁₀ alkyl.
 91. A compound of claim 90, wherein said alkyl isC₂-C₇ alkyl.
 92. A compound of claim 91, wherein said alkyl is C₂-C₄alkyl.
 93. A compound of claim 92, wherein R¹ and R² are independentlyselected from the group consisting of ethyl, n-propyl, n-butyl, andisobutyl.
 94. A compound of claim 1, wherein R³ and R⁴ are independentlyselected from the group consisting of H and OR⁹.
 95. A compound of claim94, wherein R⁹ is H.
 96. A compound of claim 1, wherein one of R⁷ or R⁸is H.
 97. A compound of claim 96, wherein both R⁷ and R⁸ are H.
 98. Acompound of the formula (III)

wherein q and r are independently integers from 0 to 4; d and e areindependently integers from 0 to 2; t and u are independently integersfrom 0 to 4; R¹, R^(1A), R², and R^(2A) are independently selected fromthe group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl,alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,(polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl,haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino,alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substitutedwith one or more substituent selected from the group consisting of OR⁹,NR⁹R¹⁰, N⁺R⁹R¹⁰R^(w)A⁻, SR⁹, S⁺R⁹A-. P⁺R⁹R¹⁰R¹¹A⁻, S(O)R⁹, SO₂R⁹, SO₃R⁹,CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, wherein alkyl, alkenyl, alkynyl,alkylaryl, alkoxy, alkoxyalkyl, polyalkyl, aryl, and cycloalkyloptionally have one or more carbons replaced by O, NR⁹, N⁺R⁹R¹⁰A-, S,SO, SO₂, S⁺R⁹A-, P⁺R⁹R¹⁰A-, or phenylene, wherein R⁹, R¹⁰ ₁₀ and R^(w)are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl,alkylammoniumalkyl, and arylalkyl; or R¹ and R² taken together with thecarbon to which they are attached form C₃-C₁₀ cycloalkylidene, or R^(1A)and R^(2A) taken together with the carbon to which they are attachedform C₃-C₁₀ cycloalkylidene; R³, R^(3A), R⁴, and R^(4A) areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, acyloxy, aryl, heterocycle, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹,and SO₃R⁹, wherein R⁹ and R¹⁰ are as defined above; or R³ and R⁴together form ═O, ═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or ═CR¹¹R¹², or R^(3A)and R^(4A) together form ═O, ═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or ═CR¹¹R¹²,wherein R¹¹ and R¹² are independently selected from the group consistingof H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl,cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen,oxo, and CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above, providedthat both R³ and R⁴ cannot be OH, NH2, and SH, or R¹¹ and R¹² togetherwith the nitrogen or carbon atom to which they are attached form acyclic ring; wherein A⁻ is a pharmaceutically acceptable anion and M isa pharmaceutically acceptable cation; R⁷, R^(7A), R⁸, and R^(8A) areindependently selected from the group consisting of hydrogen and alkyl;and one or more R^(x) and R^(xA) are independently selected from thegroup consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy,aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle,heterocycle, polyether, quaternary heterocycle, quaternary heteroaryl,OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, S(O)₂R¹³, SO₃R¹³, S⁺R¹³R¹⁴A-, NR¹³OR¹⁴,NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³,C(O)NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)OM, COR¹³, OR¹⁸, S(O)_(n)NR¹⁸, NR¹³R¹⁸,N¹⁸OR¹⁴, N⁺R⁹R¹¹R¹²A⁻, P^(+ R) ⁹R¹¹R¹²A⁻, amino acid, peptide,polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl,polyether, quaternary heterocycle, and quaternary heteroaryl can befurther substituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹,SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰,PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein R¹⁸ isselected from the group consisting of acyl, arylalkoxycarbonyl,arylalkyl, heterocycle, heterocycle, alkyl, wherein acyl,arylalkoxycarbonyl, arylalkyl, heterocycle, heterocycle, alkylquaternary heterocycle, and quaternary heteroaryl optionally aresubstituted with one or more substituent selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo,CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, andC(O)OM, wherein in R^(x) and R^(xA), one or more carbons are optionallyreplaced by O, NR¹³, N⁺R¹³R¹⁴A-, S, SO, SO₂, S⁺R¹³A-, PR¹³, P(O)R13,P⁺R¹³R¹⁴A-, phenylene, amino acid, peptide, polypeptide, carbohydrate,polyether, or polyalkyl, wherein in said polyalkyl, phenylene, aminoacid, peptide, polypeptide, and carbohydrate, one or more carbons areoptionally replaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A-, PR⁹,P⁺R⁹R¹⁰A-, or P(O)R⁹; wherein quaternary heterocycle and quaternaryheteroaryl are optionally substituted with one or more groups selectedfrom the group consisting of alkyl, alkenyl, alkynyl, polyalkyl,polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen,oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴,NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴,C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R15A-, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, andN⁺R⁹R¹¹R¹²A⁻, R¹⁹ is selected from the group consisting of alkane diyl,alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl,polyalkoxy diyl, carbohydrate, amino acid, and peptide, polypeptide,wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxydiyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, andpeptide polypeptide, can optionally have one or more carbon replaced byO, NR⁷, N⁺R⁷R⁸, S, SO, SO², S⁺R⁷R⁸, PR⁷, P⁺R⁷R⁸, phenylene, heterocycle,quatarnary heterocycle, quaternary heteroaryl, or aryl, wherein alkanediyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyetherdiyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, andpolypeptide can be substituted with one or more substituent groupsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³,NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴,C(O)NR¹³R¹⁴, C(O)OM, COR₁₃, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R15A-, P(OR¹³)OR¹⁴,S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻; wherein one or more R^(y) and R^(yA) areindependently selected from from the group consisting of H, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle,OR⁹, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein alkyl, alkenyl, alkynyl,aryl, cycloalkyl, and heterocycle can be substituted with one or moresubstituent groups independently selected from the group consisting ofalkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³,S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM,SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴,P⁺R¹³R¹⁴R15A-, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻, wherein saidalkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,cycloalkyl, and heterocycle can be further substituted with one or moresubstituent groups selected from the group consisting of OR⁷, NR⁷R⁸,SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A-, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternaryheterocycle, quaternary heteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸A⁻, andP(O)(OR⁷)OR⁸, and wherein said alkyl, alkenyl, alkynyl, polyalkyl,polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionallyhave one or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A-, S, SO, SO₂,S⁺R⁷A-, PR⁷, P(O)R⁷, P⁺R⁷R⁸A-, or phenylene.
 99. A compound of claim 98,wherein R¹, R^(1A), R², and R^(2A) are independently selected from thegroup consisting of H and alkyl.
 100. A compound of claim 99, whereinR¹, R^(1A), R², and R^(2A) are independently selected from the groupconsisting of H and C₁-C₁₀ alkyl.
 101. A compound of claim 100, whereinsaid alkyl is a C₂-C₇ alkyl.
 102. A compound of claim 101, wherein R¹,R^(1A), R², and R²A are independently C₂-C₄ alkyl.
 103. A compound ofclaim 102, wherein R¹, R^(1A), R², and R^(2A) are independently selectedfrom the group consisting of ethyl, n-propyl, n-butyl, and isobutyl.104. A compound of claim 98, wherein R³, R^(3A), R⁴, and R^(4A) areindependently selected from the group consisting of H and OR⁹.
 105. Acompound of claim 104, wherein R⁹ is H.
 106. A compound of claim 98,wherein R⁷, R^(7A), R⁸, and R^(8A) are H.
 107. A compound of claim 98,wherein d and e are independently 1 or
 2. 108. A compound of claim 107,wherein d and e are both
 2. 109. A compound of claim 98, wherein one ormore R^(x) and one or more R^(xA) are independently selected from thegroup consisting of alkyl, aryl, cycloalkyl, heterocycle, polyalkyl,acyloxy, polyether, halogen, OR¹³, NR¹³R¹⁴, NR¹³NR¹⁴R¹⁵, N⁺R⁹R¹¹R¹²A⁻,SR¹³, S⁺R¹³R¹⁴, CO₂R¹³, NR¹⁴C(O)R¹³, and NR¹⁴C(O)R¹³, wherein alkyl,aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, and polyether, can befurther substituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹,SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰ SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷,P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein in R^(x), one or morecarbons are optionally replaced by O, NR¹³, N⁺R¹³R¹⁴A-, S, SO, SO₂,S⁺R¹³A-, PR¹³, P(O)R₁₃, P⁺R¹³R¹⁴A-, phenylene, amino acid, peptide,polypeptide, carbohydrate, polyether, or polyalkyl, and wherein in saidpolyalkyl, phenylene, amino acid, peptide, polypeptide, andcarbohydrate, one or more carbons are optionally replaced by O, NR⁹,NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A-, PR⁹, P⁺R⁹R¹⁰A-, or P(O)R⁹.
 110. Acompound of claim 98, wherein one or more R^(y) and one or more R^(yA)are independently selected from the group consisting of alkyl,polyether, fluoride, chloride, bromide, iodide, NR¹³R¹⁴, NR¹⁴C(O)R¹³,and OR¹³, wherein alkyl and polyether can be further substituted withSO₃R⁹, N⁺R⁹R¹¹R¹²A⁻, and quaternary heteroaryl.
 111. A compound of claim98, wherein R¹⁹ is selected from the group consisting of alkane diyl,polyalkane diyl, alkoxy diyl, and polyalkoxy diyl, wherein alkane diyland polyalkane diyl can optionally have one or more carbon replaced byO, NR7, N+R7R8, S, SO, SO2, S+R7R8, PR7, P+R7R8, or phenylene.
 112. Acompound of claim 111, wherein R¹⁹ is selected from the group consistingof alkoxy diyl and polyalkoxydiyl wherein one or more carbons areoptionally replaced by O, NR⁹, N⁺R⁹R¹⁰, S, SO, SO₂, S⁺R⁹R¹⁰, PR⁹,P⁺R⁹R¹⁰, phenylene, amino acid, peptide, polypeptide, carbohydrate, orpolyalkyl.
 113. A compound of claim 112, wherein R¹, R^(1A), R², andR^(2A) are independently selected from the group consisting of H andalkyl.
 114. A compound of claim 113, wherein R³, R^(3A), R⁴, and R^(4A)are independently selected from the group consisting of H and OR⁹. 115.A compound of claim 114, wherein R⁹ is H.
 116. A compound of claim 115,wherein R⁷, R^(7A), R⁸, and R^(8A) are each H.
 117. A compound of claim116, wherein d and e are independently 1 or
 2. 118. A compound of claim117, wherein one or more R^(x) and one or more R^(xA) are independentlyselected from the group consisting of alkyl, aryl, cycloalkyl,heterocycle, polyalkyl, acyloxy, polyether, halogen, OR¹³, NR¹³R¹⁴R¹⁵,N⁺R⁹R¹¹R¹²A⁻, SR¹³, S⁺R¹³R¹⁴, CO₂R¹³, NR¹⁴C(O)R¹³, and NR¹⁴C(O)R¹³,wherein alkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, andpolyether, can be further substituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻,SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰ SO₂OM,SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and whereinin R^(x), one or more carbons are optionally replaced by O, NR¹³,N⁺R¹³R¹⁴A- S, SO, SO₂, S⁺R¹³A-, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A-, phenylene,amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl,and wherein in said polyalkyl, phenylene, amino acid, peptide,polypeptide, and carbohydrate, one or more carbons are optionallyreplaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A-, PR⁹, P⁺R⁹R¹⁰A-, orP(O)R⁹.
 119. A compound of claim 118, wherein one or more R^(y) and oneor more R^(yA) are independently selected from the group consisting ofalkyl, polyether, fluoride, chloride, bromide, iodide, NR¹³R¹⁴,NR¹⁴C(O)R¹³, and OR¹³, wherein alkyl and polyether can be furthersubstituted with SO₃R⁹, N⁺R⁹R¹¹R¹²A⁻, and quaternary heteroaryl.
 120. Acompound of claim 119, having the formula:

PEG=3400 molecular weight polyethylene glycol polymer chain
 121. Acompound of the formula (IV)

wherein: q and r are independently integers from 0 to 3; d and e areindependently integers from 0 to 2; t and u are independently integersfrom 0 to 5; R¹, R^(1A), R², and R^(2A) are independently selected fromthe group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl,alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,(polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl,haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino,alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substitutedwith one or more substituent selected from the group consisting of OR⁹,NR⁹R¹⁰, N⁺R⁹R¹⁰R^(w)A⁻, SR⁹, S⁺R⁹A-. P⁺R⁹R¹⁰R¹¹A⁻, S(O) R⁹, SO₂R⁹,SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, wherein alkyl, alkenyl,alkynyl, alkylaryl, alkoxy, alkoxyalkyl, polyalkyl, aryl, and cycloalkyloptionally have one or more carbons replaced by O, NR⁹, N⁺R⁹R¹⁰A-, S,SO, SO₂, S⁺R⁹A-, P⁺R⁹R¹⁰A-, or phenylene, wherein R⁹, R¹⁰, and R^(w) areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl,alkylammoniumalkyl, and arylalkyl; or R¹ and R² taken together with thecarbon to which they are attached form C₃-C₁₀ cycloalkylidene, or R^(1A)and R^(2A) taken together with the carbon to which they are attachedform C₃-C₁₀ cycloalkylidene; R³, R^(3A), R⁴, and R^(4A) areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, acyloxy, aryl, heterocycle, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹,and SO₃R⁹, wherein R⁹ and R¹⁰ are as defined above; or R³ and R⁴together form ═O, ═NOR¹¹, ═S, ═NNR¹R¹², ═NR⁹, or ═CR¹¹R¹², or R^(3A) andR^(4A) together form ═O, ═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or ═CR¹¹R¹²,wherein R¹¹ and R¹² are independently selected from the group consistingof H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl,cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen,oxo, and CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above, providedthat both R³ and R⁴ cannot be OH, NH2, and SH, or R¹¹ and R¹² togetherwith the nitrogen or carbon atom to which they are attached form acyclic ring; wherein A⁻ is a pharmaceutically acceptable anion and M isa pharmaceutically acceptable cation; R⁷, R^(7A), R⁸, and R^(8A) areindependently selected from the group consisting of hydrogen and alkyl;and one or more R^(x) and R^(xA) are independently selected from thegroup consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy,aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle,heterocycle, polyether, quaternary heterocycle, quaternary heteroaryl,OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, S(O)₂R¹³, SO₃R¹³, S⁺R¹³R¹⁴A-, NR¹³OR¹⁴,NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³,C(O)NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)OM, COR¹³, OR¹⁸, S(O)_(n)NR¹⁸, NR¹³R¹⁸,NR¹⁸OR¹⁴, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, amino acid, peptide, polypeptide,and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl,polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether,quaternary heterocycle, and quaternary heteroaryl can be furthersubstituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹,oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷,P⁺R⁹R¹¹R¹²A⁻, SR⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein R¹⁸ is selected fromthe group consisting of acyl, arylalkoxycarbonyl, arylalkyl,heterocycle, heterocycle, alkyl, wherein acyl, arylalkoxycarbonyl,arylalkyl, heterocycle, heterocycle, alkyl quaternary heterocycle, andquaternary heteroaryl optionally are substituted with one or moresubstituent selected from the group consisting of OR⁹, NR⁹R¹⁰,N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen,CONR⁹R¹⁰, SO₃R⁹, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)R¹⁷, and C(O)OM, wherein inR^(x) and R^(xA), one or more carbons are optionally replaced by O,NR¹³, N⁺R¹³R¹⁴A-, S, SO, SO₂, S⁺R¹³A-, PR¹³, P(O)R13, P⁺R¹³R¹⁴A-,phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, orpolyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide,polypeptide, and carbohydrate, one or more carbons are optionallyreplaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A-, PR⁹, P⁺R⁹R¹⁰A-, orP(O)R⁹; wherein quaternary heterocycle and quaternary heteroaryl areoptionally substituted with one or more groups selected from the groupconsisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³,NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³,P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,R¹⁹ is selected from the group consisting of alkane diyl, alkene diyl,alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxydiyl, carbohydrate, amino acid, and peptide, polypeptide, wherein alkanediyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyetherdiyl, polyalkoxy diyl, carbohydrate, amino acid, and peptidepolypeptide, can optionally have one or more carbon replaced by O, NR⁷,N⁺R⁷R⁸, S SO, SO², S⁺R⁷R⁸, PR⁷, P⁺R⁷R⁸, phenylene, heterocycle,quatarnary heterocycle, quaternary heteroaryl, or aryl, wherein alkanediyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyetherdiyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, andpolypeptide can be substituted with one or more substituent groupsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³,NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴,C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R15A-, P(OR¹³)OR¹⁴,S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻; wherein said alkyl, alkenyl, alkynyl,polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle canbe further substituted with one or more substituent groups selected fromthe group consisting of OR⁷ NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN,oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl,P(O)R⁷R⁸, P⁺R⁷R⁸A⁻, and P(O) (OR⁷)OR⁸, and wherein said alkyl, alkenyl,alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, andheterocycle can optionally have one or more carbons replaced by O, NR⁷,N⁺R⁷R⁸A-, S, SO, SO₂, S⁺R⁷A-, PR⁷, P(O)R⁷, P⁺R⁷R⁸A-, or phenylene. 122.A compound of claim 121, wherein R¹, R^(1A), R², and R^(2A) areindependently selected from the group consisting of H and alkyl.
 123. Acompound of claim 122, wherein R¹, R^(1A), R², and R^(2A) areindependently selected from the group consisting of H and C₁-C₁₀ alkyl.124. A compound of claim 123, wherein said alkyl is a C₂-C₇ alkyl. 125.A compound of claim 124, wherein R¹, R^(1A), R², and R^(2A) areindependently C₂-C₄ alkyl.
 126. A compound of claim 125, wherein R¹,R^(1A), R², and R^(2A) are independently selected from the groupconsisting of ethyl, n-propyl, n-butyl, and isobutyl.
 127. A compound ofclaim 125, wherein R³, R^(3A), R⁴, and R^(4A) are independently selectedfrom the group consisting of H and OR⁹.
 128. A compound of claim 127,wherein R⁹ is H.
 129. A compound of claim 121, wherein R⁷, R^(7A), R⁸,and R^(8A) are H.
 130. A compound of claim 121, wherein d and e areindependently 1 or
 2. 131. A compound of claim 130, wherein d and e areboth
 2. 132. A compound of claim 121, wherein one or more R^(x) and oneor more R^(xA) are independently selected from the group consisting ofalkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, polyether,halogen, OR¹³, NR¹³R¹⁴, NR¹³NR¹⁴R¹⁵, N⁺R⁹R¹¹R¹²A⁻, SR¹³, S⁺R¹³R¹⁴,CO₂R¹³, NR¹⁴C(O)R¹³, and NR¹⁴C(O)R¹³, wherein alkyl, aryl, cycloalkyl,heterocycle, polyalkyl, acyloxy, and polyether, can be furthersubstituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹,oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷,P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein in R^(x), one or morecarbons are optionally replaced by O, NR¹³, N⁺R¹³R¹⁴A-, S, SO, SO₂,S⁺R¹³A-, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A-, phenylene, amino acid, peptide,polypeptide, carbohydrate, polyether, or polyalkyl, and wherein in saidpolyalkyl, phenylene, amino acid, peptide, polypeptide, andcarbohydrate, one or more carbons are optionally replaced by O, NR⁹,N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A-, PR⁹, P⁺R⁹R¹⁰A-, or P(O)R⁹.
 133. Acompound of claim 121, wherein one or more R_(y) and one or more R_(yA)are independently selected from the group consisting of alkyl,polyether, fluoride, chloride, bromide, iodide, NR¹³R¹⁴, NR¹⁴C(O)R¹³,and OR¹³, wherein alkyl and polyether can be further substituted withSO₃R⁹, N⁺R⁹R¹¹R¹²A⁻, and quaternary heteroaryl.
 134. A compound of claim121, wherein R¹⁹ is selected from the group consisting of alkane diyl,polyalkane diyl, alkoxy diyl, and polyalkoxy diyl, wherein alkane diyland polyalkane diyl can optionally have one or more carbon replaced byO, NR7, N+R7R8, S, SO, SO2, S+R7R8, PR7, P+R7R8, or phenylene.
 135. Acompound of claim 134, wherein R¹⁹ is selected from the group consistingof alkoxy diyl and polyalkoxydiyl wherein one or more carbons areoptionally replaced by O, NR⁹, N⁺R⁹R¹⁰, S, SO, SO₂, S⁺R⁹R¹⁰, PR⁹,P⁺R⁹R¹⁰, phenylene, amino acid, peptide, polypeptide, carbohydrate, orpolyalkyl.
 136. A compound of claim 135, wherein R¹, R^(1A), R², andR^(2A) are independently selected from the group consisting of H andalkyl.
 137. A compound of claim 136, wherein R³, R^(3A), R⁴, and R^(4A)are independently selected from the group consisting of H and OR⁹. 138.A compound of claim 137, wherein R⁹ is H.
 139. A compound of claim 138,wherein R⁷, R^(7A), R⁸, and R^(8A) are each H.
 140. A compound of claim139, wherein d and e are independently 1 or
 2. 141. A compound of claim140, having the formula:

PEG 3400 molecular weight polyethylene glycol polymer chain
 142. Acompound of formula (V) substituted with SO₃R⁹, N⁺R⁹R R A , andquaternary

wherein: q is an integer from 0 to 4; r is an integer from 0 to 3; d ande are independently integers from 0 to 2; t is an integer from 0 to 4; uis an integer from 0 to 5; R¹, R^(1A), R², and R^(2A) are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl,haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino,alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl,alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally aresubstituted with one or more substituent selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R^(w)A⁻, SR⁹, S⁺R⁹A-. P⁺R⁹R¹⁰R¹¹A⁻,S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, whereinalkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, polyalkyl,aryl, and cycloalkyl optionally have one or more carbons replaced by O,NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A-, P⁺R⁹R¹⁰A-, or phenylene, wherein R⁹,R¹⁰, and R^(w) are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle,ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; or R¹ and R² takentogether with the carbon to which they are attached form C₃-C₁Ocycloalkylidene, or R^(1A) and R^(2A) taken together with the carbon towhich they are attached form C₃-C₁₀ cycloalkylidene; R³, R^(3A), R⁴, andR^(4A) are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹,SO₂R⁹, and SO₃R⁹, wherein R⁹ and R¹⁰ are as defined above; or R³ and R⁴together form ═O, ═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or ═CR¹¹R¹², or R^(3A)and R⁴ together form ═O, ═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or ═CR¹¹R¹²,wherein R¹¹ and R¹² are independently selected from the group consistingof H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl,cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen,oxo, and CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above, providedthat both R³ and R⁴ cannot be OH, NH2, and SH, or R¹¹ and R¹² togetherwith the nitrogen or carbon atom to which they are attached form acyclic ring; wherein A⁻ is a pharmaceutically acceptable anion and M isa pharmaceutically acceptable cation; R⁷, R^(7A), R⁸, and RBA areindependently selected from the group consisting of hydrogen and alkyl;and one or more R^(x) and R^(xA) are independently selected from thegroup consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy,aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle,heterocycle, polyether, quaternary heterocycle, quaternary heteroaryl,OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, S(O)₂R¹³, SO₃R¹³, S⁺R¹³R¹⁴A-, NR¹³OR¹⁴,NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³,C(O)NR¹³R¹⁴, NR14C(O)R13, C(O)OM, COR¹³, OR¹⁸, S(O)_(n)NR¹⁸, NR¹³R¹⁸,NR¹⁸OR¹⁴, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, amino acid, peptide, polypeptide,and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl,polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether,quaternary heterocycle, and quaternary heteroaryl can be furthersubstituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹,oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷,P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein R¹⁸ is selected from thegroup consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle,heterocycle, alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl,heterocycle, heterocycle, alkyl quaternary heterocycle, and quaternaryheteroaryl optionally are substituted with one or more substituentselected from the group consisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹,S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM,SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, and C(O)OM, wherein in R^(x) and R^(xA), one ormore carbons are optionally replaced by O, NR¹³, N⁺R¹³R¹⁴A⁻, S, SO, SO₂,S⁺R¹³A⁻, PR¹³, P(O)R¹³P⁺R¹³R¹⁴A, phenylene, amino acid, peptide,polypeptide, carbohydrate, polyether, or polyalkyl, wherein in saidpolyalkyl, phenylene, amino acid, peptide, polypeptide, andcarbohydrate, one or more carbons are optionally replaced by O, NR⁹,N⁺R⁹R¹⁰A-, SO, SO₂, S⁺R⁹A-, PR⁹, P⁺R⁹R¹⁰A-, or P(O) R⁹; whereinquaternary heterocycle and quaternary heteroaryl are optionallysubstituted with one or more groups selected from the group consistingof alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³,S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM,SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R15A-, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻, R¹⁹ is selected from thegroup consisting of alkane diyl, alkene diyl, alkyne diyl, polyalkanediyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, aminoacid, and peptide, polypeptide, wherein alkane diyl, alkene diyl, alkynediyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl,carbohydrate, amino acid, and peptide polypeptide, can optionally haveone or more carbon replaced by O, NR⁷, N⁺R⁷R⁸, S, SO, SO₂, S⁺R⁷R⁸, PR⁷,P⁺R⁷R⁸, phenylene, heterocycle, quatarnary heterocycle, quaternaryheteroaryl, or aryl, wherein alkane diyl, alkene diyl, alkyne diyl,polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl,carbohydrate, amino acid, peptide, and polypeptide can be substitutedwith one or more substituent groups independently selected from thegroup consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³,NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)RR¹³R¹⁴, P⁺R¹³R¹⁴R15A-, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻;wherein one or more RI and R_(yA) are independently selected from fromthe group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycle, quaternary heterocycle, OR⁹, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹,wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, and heterocycle canbe substituted with one or more substituent groups independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³,NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴,C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A^(—), P(OR¹³)OR¹⁴,S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻, wherein said alkyl, alkenyl, alkynyl,polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle canbe further substituted with one or more substituent groups selected fromthe group consisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷,CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl,P(O)R⁷R⁸, P⁺R⁷R⁸A⁻, and P(O) (OR⁷)OR⁸, and wherein said alkyl, alkenyl,alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, andheterocycle can optionally have one or more carbons replaced by O, NR⁷,N⁺R⁷R⁸A-, S, SO, SO₂, S⁺R⁷A-, PR⁷, P(O)R⁷, P⁺R⁷R⁸A-, or phenylene. 143.A compound of claim 142, wherein R¹, R^(1A), R², and R^(2A) areindependently selected from the group consisting of H and alkyl.
 144. Acompound of claim 143, wherein R¹, R^(1A), R², and R^(2A) areindependently selected from the group consisting of H and C₁-C₁₀ alkyl.145. A compound of claim 144, wherein said alkyl is a C₂-C₇ alkyl. 146.A compound of claim 145, wherein R¹, R^(1A), R², and R^(2A) areindependently C₂-C₄ alkyl.
 147. A compound of claim 146, wherein R¹,R^(1A), R², and R^(2A) are independently selected from the groupconsisting of ethyl, n-propyl, n-butyl, and isobutyl.
 148. A compound ofclaim 142, wherein R³, R^(3A), R⁴, and R^(4A) are independently selectedfrom the group consisting of H and OR⁹.
 149. A compound of claim 148,wherein R⁹ is H.
 150. A compound of claim 142, wherein R⁷, R^(7A), R⁸,and R^(8A) are H.
 151. A compound of claim 142, wherein d and e areindependently 1 or
 2. 152. A compound of claim 151, wherein d and e areboth
 2. 153. A compound of claim 142, wherein one or more R^(x) and oneor more R^(xA) are independently selected from the group consisting ofalkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, polyether,halogen, OR¹³, NR¹³R¹⁴, NR¹³N¹⁴R¹⁵, N⁺R⁹R¹¹R¹²A⁻, SR¹³, S⁺R¹³R¹⁴,CO₂R¹³, NR¹⁴C(O)R¹³, and NR¹⁴C(O)R¹³, wherein alkyl, aryl, cycloalkyl,heterocycle, polyalkyl, acyloxy, and polyether, can be furthersubstituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹,oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰ SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷,P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein in R^(x), one or morecarbons are optionally replaced by O, NR¹³, N⁺R¹³R¹⁴A-, S, SO, SO₂,S⁺R¹³A-, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A-, phenylene, amino acid, peptide,polypeptide, carbohydrate, polyether, or polyalkyl, and wherein in saidpolyalkyl, phenylene, amino acid, peptide, polypeptide, andcarbohydrate, one or more carbons are optionally replaced by O, NR⁹,N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A-, PR⁹, PR⁹R¹⁰A-, or P(O)R⁹.
 154. A compoundof claim 142, wherein one or more R^(y) and one or more R_(yA) areindependently selected from the group consisting of alkyl, polyether,fluoride, chloride, bromide, iodide, NR¹³R¹⁴, NR¹⁴C(O)R¹³, and OR¹³,wherein alkyl and polyether can be further substituted with SO₃R⁹,N⁺R⁹R¹¹R¹²A⁻, and quaternary heteroaryl.
 155. A compound of claim 142,wherein R¹⁹ is selected from the group consisting of alkane diyl,polyalkane diyl, alkoxy diyl, and polyalkoxy diyl, wherein alkane diyland polyalkane diyl can optionally have one or more carbon replaced byO, NR7, N+R7R8, S, SO, SO2, S+R7R8, PR7, P+R7R8, or phenylene.
 156. Acompound of claim 155, wherein R¹⁹ is selected from the group consistingof alkoxy diyl and polyalkoxydiyl wherein one or more carbons areoptionally replaced by O, NR⁹, N⁺R⁹R¹⁰, S, SO, SO₂, S⁺R⁹R¹⁰, PR⁹,P⁺R⁹R¹⁰, phenylene, amino acid, peptide, polypeptide, carbohydrate, orpolyalkyl.
 157. A compound of claim 156, wherein R¹, R^(1A), R², andR^(2A) are independently selected from the group consisting of H andalkyl.
 158. A compound of claim 157, wherein R³, R^(3A), R⁴, and R^(4A)are independently selected from the group consisting of H and OR⁹. 159.A compound of claim 158, wherein R⁹ is H.
 160. A compound of claim 159,wherein R⁷, R^(7A), R⁸, and R^(8A) are each H.
 161. A compound of claim160, wherein d and e are independently 1 or
 2. 162. A compound of claim161, having the formula:

PEG =3400 molecular weight polyethylene glycol polymer chain
 163. Apharmaceutical composition comprising an anti-hyperlipidemic conditioneffective amount of a compound of formula (I) of claim 1, and apharmaceutically acceptable carrier.
 164. A pharmaceutical compositioncomprising an anti-atherosclerotic effective amount of a compound offormula (I) of claim 1, and a pharmaceutically acceptable carrier. 165.A pharmaceutical composition comprising an anti-hypercholesterolemiaeffective amount of a compound of formula (I) of claim 1, and apharmaceutically acceptable carrier.
 166. A method for the prophylaxisor treatment of a hyperlipidemic condition comprising administering to apatient in need thereof a composition of claim 164 in unit dosage form.167. A method for the prophylaxis or treatment of an atheroscleroticcondition comprising administering to a patient in need thereof acomposition of claim 165 in unit dosage form.
 168. A method for theprophylaxis or treatment of hypercholesterolemia comprisingadministering to a patient in need thereof a composition of claim 166 inunit dosage form.
 169. A compound of formula 1:

wherein: q is an integer from 1 to 4; n is an integer from 0 to 2; R¹and R² are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl,alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R^(w)A⁻, SR⁹, S⁺R⁹R¹⁰R¹¹A⁻, S(O)R⁹,SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, wherein alkyl,alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, andcycloalkyl optionally have one or more carbons replaced by O, NR⁹,N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻, P⁺R⁹R¹A⁻, or phenylene, wherein R⁹, R¹ ,and R^(w) are independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle,ammoniumalkyl, arylalkyl, and alkylammoniumalkyl; or R¹ and R² takentogether with the carbon to which they are attached form C₃-C₁₀cycloalkyl; R³ and R⁴ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle,OR⁹, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein R⁹ and R¹⁰ are as definedabove; or R³ and R⁴ together form ∇O, ═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or═CR¹¹R¹², wherein R¹¹ and R¹² are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl,cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen,oxo, and CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above, providedthat both R³ and R⁴ cannot be OH, NH₂, and SH, or R¹¹ and R¹² togetherwith the nitrogen or carbon atom to which they are attached form acyclic ring; R⁵ is selected from the group consisting of H, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle,OR⁹, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein alkyl, alkenyl, alkynyl,aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternaryheteroaryl can be substituted with one or more substituent groupsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo,OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵,NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³,P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,wherein: A⁻ is a pharmaceutically acceptable anion and M is apharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl,polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle canbe further substituted with one or more substituent groups selected fromthe group consisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷,CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹ A-, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternaryheteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸R⁹A⁻, and P(O)(OR⁷)OR⁸, and wherein saidalkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,cycloalkyl, and heterocycle can optionally have one or more carbonsreplaced by O, NR⁷, N⁺R⁷R⁸A-, S, SO, SO₂, S⁺R⁷A-, PR⁷, P(O)R⁷, P⁺R⁷R⁸A-,or phenylene, and R¹³, R¹⁴, and R¹⁵ are independently selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl,arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle,quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl,alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally haveone or more carbons replaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻,PR⁹, P⁺R⁹R¹⁰A-, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, orpolypeptide, and R¹³, R¹⁴, and R¹⁵ are optionally substituted with oneor more groups selected from the group consisting of sulfoalkyl,quaternary heterocycle, quaternary heteroaryl, OR⁹, NR⁹R¹⁰,N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen,CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(R¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A-, S⁺R⁹R¹⁰A-, andC(O)OM, wherein R¹⁶ and R¹⁷ are independently selected from thesubstituents constituting R⁹ and M; or R¹⁴ and R¹⁵, together with thenitrogen atom to which they are attached, form a cyclic ring; and R⁶ ishydroxy; and R⁷ and R⁸ are independently selected from the groupconsisting of hydrogen and alkyl; and one or more R^(x) areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl,cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle,quaternary heteroaryl, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, S(O)₂R¹³, SO₃R¹³,S⁺R¹³R¹⁴A-, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM,SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)OM, COR¹³, OR¹⁸,S(O)_(n)NR¹⁸, NR¹³R¹⁸, NR¹⁸OR¹⁴, O⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, amino acid,peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl,polyether, quaternary heterocycle, and quaternary heteroaryl can befurther substituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹,SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰,PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein R¹⁸ isselected from the group consisting of acyl, arylalkoxycarbonyl,arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl,arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,quaternary heterocycle, and quaternary heteroaryl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo,CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, andC(O)OM, wherein in R^(x), one or more carbons are optionally replaced byO, NR¹³, N⁺R¹³R¹⁴A-, S, SO, SO₂, S⁺R¹³A⁻, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A-,phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, orpolyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide,polypeptide, and carbohydrate, one or more carbons are optionallyreplaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A-, PR⁹, P⁺R⁹R¹⁰A-, orP(O)R⁹; wherein quaternary heterocycle and quaternary heteroaryl areoptionally substituted with one or more groups selected from the groupconsisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³,NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³,P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,provided that both R⁵ and R⁶ cannot be hydrogen, OH, or SH; providedthat when R⁵ is phenyl, only one of R¹ or R² is H; or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof.
 170. A compound of formulaI:

wherein: q is 1 or 2; n is 2; R¹ and R² are each alkyl; R³ is hydroxy;R⁴ and R⁶ are hydrogen; R⁵ has the formula (II)

wherein t is an integer from 0 to 5; one or more R^(y) are OR¹³; R¹³ isselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl,quaternary heterocycle, quaternary heteroaryl, and quaternaryheteroarylalkyl; said R¹³ alkyl, alkenyl, alkynyl, arylalkyl,heterocycle, and polyalkyl groups optionally have one or more carbonsreplaced by O, NR⁹, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻, PR⁹, P⁺R⁹R¹⁰A⁻,P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, or polypeptide;R¹³ is optionally substituted with one or more groups selected from thegroup consisting of sulfoalkyl, quaternary heterocycle, quaternaryheteroaryl, OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo,CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷,P⁺R⁹R¹⁰R¹¹A⁻, S⁺R⁹R¹⁰A⁻, and C(O)OM, wherein A⁻ is a pharmaceuticallyacceptable anion, and M is a pharmaceutically acceptable cation, R⁹ andR¹⁰ are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl,arylalkyl, and alkylammoniumalkyl; R¹¹ and R¹² are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl,carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹,SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, wherein R⁹ and R¹⁰are as defined above, provided that both R³ and R⁴ cannot be OH, NH₂,and SH; or R¹¹ and R¹² together with the nitrogen or carbon atom towhich they are attached form a cyclic ring; and R¹⁶ and R¹⁷ areindependently selected from the substituents constituting R⁹ and M; R⁷and R⁸ are hydrogen; and one or more R^(x) are independently selectedfrom the group consisting of alkoxy, alkylamino and dialkylamino; or apharmaceutically acceptable salt, solvate, or prodrug thereof.
 171. Acompound of claim 170 wherein R¹ and R² are each n-butyl.
 172. Acompound of claim 171 wherein t is 1, R^(y) is OR¹³, and R¹³ is asdefined in claim
 170. 173. A compound of claim 172 wherein one or moreR^(x) are independently selected from methoxy and dimethylamino.
 174. Acompound of claim 172 wherein R^(x) is dimethylamino.
 175. A compound ofclaim 172 wherein: t is 1; R^(y) is para-OR¹³; and R¹³ is as defined inclaim
 170. 176. A compound of claim 172 wherein: t is 1; Rl ismeta-OR¹³; and R¹³ is as defined in claim
 170. 177. A compound of claim172 having the 4R,5R configuration.
 178. A compound of claim 170 havingthe structural formula:


179. A compound of claim 170 having the structural formula:


180. A compound of formula (I):

wherein: q is an integer from 1 to 4; n is an integer from 0 to 2; R¹and R² are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl,alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R^(w)A⁻, SR⁹, S⁺R⁹R¹⁰A⁻. P⁺R⁹R¹⁰R¹¹A⁻,S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, whereinalkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl,(polyalkyl)aryl, and cycloalkyl optionally have one or more carbonsreplaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻, P⁺R⁹R¹⁰A⁻, orphenylene, wherein R⁹, R¹⁰, and R^(w) are independently selected fromthe group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl,carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, andalkylammoniumalkyl; or R¹ and R² taken together with the carbon to whichthey are attached form C₃-C₁₀ cycloalkyl; R³ and R⁴ are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl,acyloxy, aryl, heterocycle, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R , and SO₃R 9,wherein R⁹ and R₁₀ are as defined above; or R³ and R⁴ together form ═O,═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or ═CR¹¹R¹², wherein R¹¹ and R¹² areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle,carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR⁹, NR⁹R¹⁰,SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰,wherein R⁹ and R¹⁰ are as defined above, provided that both R³ and R⁴cannot be OH, NH₂, and SH, or R¹¹ and R¹² together with the nitrogen orcarbon atom to which they are attached form a cyclic ring; R⁵ is arylsubstituted with one or more OR^(13a), wherein R^(13a) is selected fromthe group consisting of polyether, aryl, alkylarylalkyl,alkylheteroarylalkyl, alkylheterocyclylalkyl, heterocyclylalkyl,heteroarylalkyl, quaternary heterocyclylalkyl, alkylammoniumalkyl, andcarboxyalkylaminocarbonylalkyl, R^(13a) is optionally substituted withone or more groups selected from the group consisting of hydroxy, amino,sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl,sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternaryheterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR⁹, NR⁹R¹⁰,N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen,CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰A-, S⁺R⁹R¹⁰A-, andC(O)OM, wherein A⁻ is an pharmaceutically acceptable anion and M is apharmaceutically acceptable cation, wherein R¹⁶ and R¹⁷ areindependently selected from the substituents constituting R⁹ and M; andR⁶ is selected from the group consisting of H, alkyl, alkenyl, alkynyl,aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR³⁰, SR⁹,S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocycle, quaternary heterocycle, and quaternaryheteroaryl can be substituted with one or more substituent groupsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo,OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵,NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³,NR¹³C(O)R¹⁴, NR¹³C(O)NR¹⁴R¹⁵, NR¹³CO₂R¹⁴, OC(O)R¹³, OC(O)NR ¹³R¹⁴,NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, NR¹³SONR¹⁴R¹⁵, NR¹³SO₂NR¹⁴R¹⁵, P(O)R¹³R¹⁴,P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻, wherein: A⁻ isa pharmaceutically acceptable anion and M is a pharmaceuticallyacceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether,aryl, haloalkyl, cycloalkyl, and heterocycle can be further substitutedwith one or more substituent groups selected from the group consistingof OR⁷ NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸,N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷R^(P)⁺R⁷R⁸R⁹A⁻, and P(O)(OR⁷)OR⁸, and wherein said alkyl, alkenyl, alkynyl,polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle canoptionally have one or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A-, S, SO,SO₂, S⁺R⁷A-, PR⁷, P(O)R⁷, P⁺R⁷R⁸A-, or phenylene, and R¹³, R¹⁴, and R¹⁵are independently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl,alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle,heteroaryl, quaternary heterocycle, quaternary heteroaryl,heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl,quaternary heteroarylalkyl, alkylammoniumalkyl, andcarboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl,arylalkyl, heterocycle, and polyalkyl optionally have one or morecarbons replaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻, PR⁹,P⁺R⁹R¹⁰A-, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, orpolypeptide, and R¹³, R¹⁴, and R¹⁵ are optionally substituted with oneor more groups selected from the group consisting of hydroxy, amino,sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl,sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternaryheterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR⁹, NR⁹R¹⁰,N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen,CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A-, S⁺R⁹R¹⁰A-, andC(O)OM, wherein R¹⁶ and R17 are independently selected from thesubstituents constituting R⁹ and M; or R¹³ and R¹⁴, together with thenitrogen atom to which they are attached form a mono- or polycyclicheterocycle that is optionally substituted with one or more radicalsselected from the group consisting of oxo, carboxy and quaternary salts;or R¹⁴ and R¹⁵, together with the nitrogen atom to which they areattached, form a cyclic ring; and R³⁰ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl,carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, andalkylammoniumalkyl; and R⁷ and R⁸ are independently selected from thegroup consisting of hydrogen and alkyl; and one or more R^(x) areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl,cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle,quaternary heteroaryl, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, S(O)₂R¹³, SO₃R¹³,S⁺R¹³R¹⁴A-, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM,SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴, NR14C(O)R13, C(O)OM, COR¹³, OR¹⁸,S(O)_(n)NR¹⁸, NR¹³R¹⁸, NR¹⁸OR¹⁴, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, amino acid,peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl,polyether, quaternary heterocycle, and quaternary heteroaryl can befurther substituted with OR⁹, NR⁹R¹⁰, N⁺ ⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹,SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰,PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein R¹⁸ isselected from the group consisting of acyl, arylalkoxycarbonyl,arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl,arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,quaternary heterocycle, and quaternary heteroaryl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo,CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, andC(O)OM, wherein in R^(x), one or more carbons are optionally replaced byO, NR¹³, N⁺R¹³R¹⁴A-, S, SO, SO₂, S⁺R¹³A⁻, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A-,phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, orpolyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide,polypeptide, and carbohydrate, one or more carbons are optionallyreplaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A-, PR⁹, P⁺R⁹R¹⁰A-, orP(O)R⁹; wherein quaternary heterocycle and quaternary heteroaryl areoptionally substituted with one or more groups selected from the groupconsisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³,NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³,P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻, ora pharmaceutically acceptable salt, solvate, or prodrug thereof.
 181. Acompound of claim 180 wherein: R⁵ is phenyl substituted with OR^(13a);R^(13a) is independently selected from the group consisting ofpolyether, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl,and carboxyalkylaminocarbonylalkyl; and R^(13a) is optionallysubstituted with one or more groups selected from the group consistingof carboxy, quaternary heterocycle, quaternary heteroaryl, and NR⁹R¹⁰.182. A compound of claim 180 wherein n is 1 or
 2. 183. A compound ofclaim 180 wherein R⁷ and R⁸ are independently selected from the groupconsisting of hydrogen and alkyl.
 184. A compound of claim 180 whereinR7 and R⁸ are hydrogen.
 185. A compound of claim 180 wherein R³ and R⁴are independently selected from the group consisting of hydrogen andOR⁹.
 186. A compound of claim 180 wherein R³ is hydrogen and R⁴ ishydroxy.
 187. A compound of claim 180 wherein one or more R^(x) areindependently selected from the group consisting of OR¹³ and NR¹³R¹⁴.188. A compound of claim 180 wherein one or more R^(x) are independentlyselected from methoxy and dimethylamino.
 189. A compound of claim 180wherein R¹ and R² are independently selected from the group consistingof hydrogen and alkyl.
 190. A compound of claim 180 wherein R¹ and R²are independently selected from the group consisting alkyl.
 191. Acompound of claim 180 wherein R¹ and R² are the same alkyl.
 192. Acompound of claim 180 wherein R¹ and R² are each n-butyl.
 193. Acompound of claim 180 wherein n is 1 or 2; R¹ and R² are n-butyl; R³ andR⁶ are hydrogen; R⁴ is hydroxy; R⁷ and R⁸ are hydrogen; and one or moreR^(x) are independently selected from methoxy and dimethylamino.
 194. Acompound of claim 180 having the structural formula:


195. A compound of claim 180 having the structural formula:


196. A compound of claim 180 having the structural formula:


197. A compound of claim 180 having the structural formula:


198. A compound of claim 180 having the structural formula:


199. A compound of claim 180 having the structural formula:


200. A compound of claim 180 having the structural formula:


201. A compound of formula (I):

wherein: q is an integer from 1 to 4; n is an integer from 0 to 2; R¹and R² are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl, whereinalkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy,alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyloptionally are substituted with one or more substituents selected fromthe group consisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R^(w)A⁻, S⁺R⁹R¹⁰A⁻.P⁺R⁹R¹⁰R¹¹A⁻, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, andCONR⁹R¹⁰, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy,alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or morecarbons replaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻, P⁺R⁹R¹⁰A⁻, orphenylene, wherein R⁹, R¹⁰, and R^(w) are independently selected fromthe group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl,carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, andalkylammoniumalkyl; or R¹ and R² taken together with the carbon to whichthey are attached form C₃-C₁₀ cycloalkyl; R³ and R⁴ are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl,acyloxy, aryl, heterocycle, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹,wherein R⁹ and R¹⁰ are as defined above; or R³ and R⁴ together form ═O,═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or ═CR¹¹R¹², wherein R¹¹ and R¹² areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle,carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR⁹, NR⁹R¹⁰,SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO2R⁹, CN, halogen, oxo, and CONR⁹R¹⁰,wherein R⁹ and R¹⁰ are as defined above, provided that both R³ and R⁴cannot be OH, NH₂, and SH, or R¹¹ and R¹² together with the nitrogen orcarbon atom to which they are attached form a cyclic ring; R⁵ is arylsubstituted with one or more OR^(13b), wherein R^(13b) is selected fromthe group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether,aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl,alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternaryheterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl,quaternary heterocyclylalkyl, quaternary heteroarylalkyl,alkylammoniumalkyl, and carboxyalkylaminocarbonylalkyl, R^(13b) issubstituted with one or more groups selected from the group consistingof hydroxy, amino, sulfo, carboxy, carboxyalkyl, heterocycle,heteroaryl, sulfoalkyl, quaternary heterocyclylalkyl, quaternaryheteroarylalkyl, or guanidinyl, and R⁶ is selected from the groupconsisting of H. alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,quaternary heterocycle, OR³⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, whereinalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternaryheterocycle, and quaternary heteroaryl can be substituted with one ormore substituent groups independently selected from the group consistingof alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternaryheteroaryl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³,NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴,C(O)NR¹³R¹⁴, C(O)OM, COR¹³, NR¹³C(O)R¹⁴, NR¹³C(O)NR¹⁴R¹⁵, NR¹³CO₂R¹⁴,OC(O)R¹³, OC(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, NR¹³SONR¹⁴R¹⁵,NR¹³SO₂NR¹⁴R¹⁵, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, andN⁺R⁹R¹¹R¹²A⁻, wherein: A⁻ is a pharmaceutically acceptable anian and Mis a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl,polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle canbe further substituted with one or more substituent groups selected fromthe group consisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷,CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl,P(O)R⁷R⁸, P⁺R⁷R⁸R⁹A⁻, and P(O)(OR⁷)OR⁸, and wherein said alkyl, alkenyl,alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, andheterocycle can optionally have one or more carbons replaced by O, NR⁷,N⁺R⁷R⁸A-, S, SO, SO₂, S⁺R⁷A-, PR⁷, P(O)R⁷, P⁺R⁷R⁸A-, or phenylene, andR¹³, R¹⁴, and R¹⁵ are independently selected from the group consistingof hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl,cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternaryheteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternaryheterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl, andcarboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl,arylalkyl, heterocycle, and polyalkyl optionally have one or morecarbons replaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R ⁹A⁻, PR⁹,P⁺R⁹R¹⁰A-, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, orpolypeptide, and R¹³, R¹⁴, and R¹⁵ are optionally substituted with oneor more groups selected from the group consisting of hydroxy, amino,sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl,sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternaryheterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR⁹, NR⁹R¹⁰,N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen,CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A-, S⁺R9R A-, andC(O)OM, wherein R¹⁶ and R¹⁷ are independently selected from thesubstituents constituting R⁹ and M; or R¹³ and R¹⁴, together with thenitrogen atom to which they are attached form a mono- or polycyclicheterocycle that is optionally substituted with one or more radicalsselected from the group consisting of oxo, carboxy and quaternary salts;or R¹⁴ and R¹⁵, together with the nitrogen atom to which they areattached, form a cyclic ring; and R³⁰ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl,carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, andalkylammoniumalkyl; and R⁷ and R⁸ are independently selected from thegroup consisting of hydrogen and alkyl; and one or more R^(x) areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl,cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle,quaternary heteroaryl, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, S(O)₂R¹³, SO₃R¹³,S⁺R¹³R¹⁴A-, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SQ2OM,SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴, NR14C(O)R13, C(O)OM, COR¹³, OR¹⁸,S(O)_(n)NR¹⁸, NR¹³R¹⁸, NR¹⁸O¹⁴, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, amino acid,peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl,polyether, quaternary heterocycle, and quaternary heteroaryl can befurther substituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹,SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰,PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein R¹⁸ isselected from the group consisting of acyl, arylalkoxycarbonyl,arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl,arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,quaternary heterocycle, and quaternary heteroaryl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo,CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, andC(O)OM, wherein in R^(x), one or more carbons are optionally replaced byO, NR¹³, N⁺R¹³R¹⁴A-, S, SO, SO₂, S⁺R¹³A⁻, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A-,phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, orpolyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide,polypeptide, and carbohydrate, one or more carbons are optionallyreplaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A-, PR⁹, P⁺R⁹R¹⁰A-, orP(O)R⁹; wherein quaternary heterocycle and quaternary heteroaryl areoptionally substituted with one or more groups selected from the groupconsisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³,NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³,P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻, ora pharmaceutically acceptable salt, solvate, or prodrug thereof.
 202. Acompound of claim 201 wherein: R⁵ is phenyl substituted with OR^(13b);R^(13b) is independently selected from the group consisting of alkyl,quaternary heteroarylalkyl, and quaternary heterocyclylalkyl; andR^(13b) is substituted with one or more groups selected from the groupconsisting of hydroxy, heterocycle, heteroaryl, and guanidinyl.
 203. Acompound of claim 201 wherein n is 1 or
 2. 204. A compound of claim 201wherein R⁷ and R⁸ are independently selected from the group consistingof hydrogen and alkyl.
 205. A compound of claim 201 wherein R⁷ and R⁸are hydrogen.
 206. A compound of claim 201 wherein R³ and R⁴ areindependently selected from the group consisting of hydrogen and OR⁹.207. A compound of claim 201 wherein R³ is hydrogen and R⁴ is hydroxy.208. A compound of claim 201 wherein one or more R^(x) are independentlyselected from the group consisting of OR¹³ and NR¹³R¹⁴.
 209. A compoundof claim 201 wherein one or more R^(x) are independently selected frommethoxy and dimethylamino.
 210. A compound of claim 201 wherein R¹ andR² are independently selected from the group consisting of hydrogen andalkyl.
 211. A compound of claim 201 wherein R¹ and R² are independentlyselected from the group consisting alkyl.
 212. A compound of claim 201wherein R¹ and R² are the same alkyl.
 213. A compound of claim 201wherein R¹ and R² are each n-butyl.
 214. A compound of claim 201 whereinn is 1 or 2; R¹ and R² are n-butyl; R³ and R⁶ are hydrogen; R⁴ ishydroxy; R⁷ and R⁸ are hydrogen; and one or more R^(x) are independentlyselected from methoxy and dimethylamino.
 215. A compound of claim 201having the structural formula:


216. A compound of claim 201 having the structural formula:


217. A compound of claim 201 having the structural formula:


218. A compound of formula (I):

wherein: q is an integer from 1 to 4; n is an integer from 0 to 2; R¹and R² are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl,alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R^(w)A⁻, SR⁹, S⁺R⁹R¹⁰A⁻. P⁺R⁹R¹⁰R¹¹A⁻,S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, whereinalkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl,(polyalkyl)aryl, and cycloalkyl optionally have one or more carbonsreplaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻, P⁺R⁹R¹⁰A⁻, orphenylene, wherein R⁹, R¹⁰, and R^(w) are independently selected fromthe group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl,carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, andalkylammoniumalkyl; or R¹ and R² taken together with the carbon to whichthey are attached form C₃-C₁₀ cycloalkyl; R³ and R⁴ are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl,acyloxy, aryl, heterocycle, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹,wherein R⁹ and R¹⁰ are as defined above; or R³ and R⁴ together form ═O,═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or ═CR¹¹R¹², wherein R¹¹ and R¹² areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle,carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR⁹, NR⁹R¹⁰,SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰,wherein R⁹ and R¹⁰ are as defined above, provided that both R³ and R⁴cannot be OH, NH₂, and SH, or R¹¹ and R¹² together with the nitrogen orcarbon atom to which they are attached form a cyclic ring; R⁵ is arylsubstituted with one or more ORl^(3b), wherein R^(13b) is selected fromthe group consisting ;of alkyl, alkenyl, alkynyl, polyalkyl, polyether,aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl,alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternaryheterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl,quaternary heterocyclylalkyl, quaternary heteroarylalkyl,alkylammoniumalkyl, and carboxyalkylaminocarbonylalkyl, R^(13b) issubstituted with one or more groups selected from the group consistingof OR^(9a), NR^(9a)R¹⁰, N⁺R^(9a)R¹¹R¹²A⁻, SR^(9a), S(O)R^(9a), S₂R^(9a),SO₃R^(9a), CO₂ ^(9a), CONR^(9a)R¹⁰, SO₂NR^(9a), S(O)R^(9a), SO₃R^(9a),CO₂R^(9a), CONR^(9a)R¹⁰, SO₂NR^(9a)R¹⁰, P⁺R^(9a)R¹⁰R¹¹A-, andS⁺R^(9a)R¹⁰A-, wherein A⁻ is an pharmaceutically acceptable anion and Mis a pharmaceutically acceptable cation, and wherein R^(9a) is selectedfrom the group consisting of carboxyalkyl, carboxyheteroaryl,carboxyheterocycle, carboalkoxyalkyl, and carboxyalkylamino; R⁶ isselected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocycle, quaternary heterocycle, OR³⁰, SR⁹, S(O)R⁹,SO₂R⁹, and SO₃R⁹, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycle, quaternary heterocycle, and quaternary heteroaryl can besubstituted with one or more substituent groups independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, polyalkyl,polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl,quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR¹³,NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³,NR¹³C(O)R¹⁴, NR¹³C(O)NR¹⁴R¹⁵, NR¹³CO₂R¹⁴, OC(O)R¹³, OC(O)NR¹³R¹⁴,NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, NR¹³SONR¹⁴R¹⁵, NR¹³SO₂NR¹⁴R¹⁵, P(O)R¹³R¹⁴,P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻, wherein: A⁻ isa pharmaceutically acceptable anion and M is a pharmaceuticallyacceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether,aryl, haloalkyl, cycloalkyl, and heterocycle can be further substitutedwith one or more substituent groups selected from the group consistingof OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸,N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷R⁸,P⁺R⁷R⁸R⁹A⁻, and P(O)(OR⁷)OR⁸, and wherein said alkyl, alkenyl, alkynyl,polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle canoptionally have one or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A-, S, SO,SO₂, S⁺R⁷A-, PR⁷, P(O)R⁷, P⁺R⁷R⁸A-, or phenylene, and R¹³, R¹⁴, and R¹⁵are independently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl,alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle,heteroaryl, quaternary heterocycle, quaternary heteroaryl,heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl,quaternary heteroarylalkyl, alkylammoniumalkyl, andcarboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl,arylalkyl, heterocycle, and polyalkyl optionally have one or morecarbons replaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻, PR⁹,P⁺R⁹R¹⁰A-, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, orpolypeptide, and R¹³, R¹⁴, and R¹⁵ are optionally substituted with oneor more groups selected from the group consisting of hydroxy, amino,sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl,sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternaryheterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR⁹, NR⁹R¹⁰,N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen,CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A-, S⁺R⁹R¹⁰ A-, andC(O)OM, wherein R¹⁶ and R¹⁷ are independently selected from thesubstituents constituting R⁹ and M; or R¹³ and R¹⁴, together with thenitrogen atom to which they are attached form a mono- or polycyclicheterocycle that is optionally substituted with one or more radicalsselected from the group consisting of oxo, carboxy and quaternary salts;or R¹⁴ and R¹⁵, together with the nitrogen atom to which they areattached, form a cyclic ring; and R³⁰ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl,carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, andalkylammoniumalkyl; and R⁷ and R⁸ are independently selected from thegroup consisting of hydrogen and alkyl; and one or more R^(x) areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl,cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle,quaternary heteroaryl, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, S(O)₂R¹³, SO₃R¹³,S⁺R¹³R¹⁴A-, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM,SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴, NR14C(O)R13, C(O)OM, COR¹³, OR¹⁸,S(O)_(n)NR¹⁸, NR¹³R¹⁸, N¹⁸OR¹⁴, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, amino acid,peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl,polyether, quaternary heterocycle, and quaternary heteroaryl can befurther substituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹,SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰,PO(OR¹⁶)OR¹⁷, P+R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein R¹⁸ isselected from the group consisting of acyl, arylalkoxycarbonyl,arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl,arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,quaternary heterocycle, and quaternary heteroaryl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo,CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM, SO₂NR⁹R¹⁰, P(OR¹⁶)OR¹⁷, andC(O)OM, wherein in R^(x), one or more carbons are optionally replaced byO, NR¹³, N⁺R¹³R¹⁴A-, S, SO, S⁺R¹³A⁻, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A-,phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, orpolyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide,polypeptide, and carbohydrate, one or more carbons are optionallyreplaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A-, PR⁹, P⁺R⁹R¹⁰A-, orP(O)R⁹; wherein quaternary heterocycle and quaternary heteroaryl areoptionally substituted with one or more groups selected from the groupconsisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³,NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³,P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻, ora pharmaceutically acceptable salt, solvate, or prodrug thereof.
 219. Acompound of claim 218 wherein: R⁵ is phenyl substituted with OR^(13b);R^(13b) is alkyl; and R^(13b) is substituted with one or more groupsselected from the group consisting of OR^(9a) and NR^(9a)R¹⁰; and R^(9a)is selected from the group consisting of carboxyalkyl,carboxyheteroaryl, and carboxyheterocycle; and R¹⁰ is carboxyalkyl. 220.A compound of claim 218 wherein n is 1 or
 2. 221. A compound of claim218 wherein R⁷ and R⁸ are independently selected from the groupconsisting of hydrogen and alkyl.
 222. A compound of claim 218 whereinR⁷ and R⁸ are hydrogen.
 223. A compound of claim 218 wherein R³ and R⁴are independently selected from the group consisting of hydrogen andOR⁹.
 224. A compound of claim 218 wherein R³ is hydrogen and R⁴ ishydroxy.
 224. A compound of claim 218 wherein one or more R^(x) areindependently selected from the group consisting of OR¹³ and NR¹³R¹⁴.226. A compound of claim 218 wherein one or more R^(x) are independentlyselected from methoxy and dimethylamino.
 227. A compound of claim 218wherein R¹ and R² are independently selected from the group consistingof hydrogen and alkyl.
 228. A compound of claim 218 wherein R¹ and R²are independently selected from the group consisting alkyl.
 229. Acompound of claim 218 wherein R¹ and R² are the same alkyl.
 230. Acompound of claim 218 wherein R¹ and R² are each n-butyl.
 231. Acompound of claim 218 wherein n is 1 or 2; R¹ and R² are n-butyl; R³ andR⁶ are hydrogen; R⁴ is hydroxy; R⁷ and R⁸ are hydrogen; and one or moreR^(x) are independently selected from methoxy and dimethylamino.
 232. Acompound of claim 218 having the structural formula:


233. A compound of claim 218 having the structural formula:


234. A compound of formula (I):

wherein: q is an integer from 1 to 4; n is an integer from 0 to 2; R¹and R² are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl,alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R^(w)A⁻, S⁺R⁹R¹⁰A⁻, P⁺R⁹R¹⁰R¹¹A⁻,S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, whereinalkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl,(polyalkyl)aryl, and cycloalkyl optionally have one or more carbonsreplaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻, P⁺R⁹R¹⁰A⁻, orphenylene, wherein R⁹, R¹⁰, and R^(w) are independently selected fromthe group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl,carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, andalkylammoniumalkyl; or R¹ and R² taken together with the carbon to whichthey are attached form C₃-C₁₀ cycloalkyl; R³ and R⁴ are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl,acyloxy, aryl, heterocycle, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹,wherein R⁹ and R¹⁰ are as defined above; or R³ and R⁴ together form ═O,═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or ═CR¹¹R¹², wherein R¹¹ and R¹² areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle,carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR⁹, NR⁹R¹⁰,SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰,wherein R⁹ and R¹⁰ are as defined above, provided that both R³ and R⁴cannot be OH, NH₂, and SH, or R¹¹ and R¹² together with the nitrogen orcarbon atom to which they are attached form a cyclic ring; R⁵ is arylsubstituted with one or more OR^(13b), wherein R^(13b) is selected fromthe group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether,aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl,alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternaryheterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl,quaternary heterocyclylalkyl, quaternary heteroarylalkyl,alkylammoniumalkyl, and carboxyalkylaminocarbonylalkyl, R^(13b) issubstituted with one or more groups selected from the group consistingof NR⁹R^(10a), CONR⁹R^(10a), SO₂NR⁹R^(10a)R¹¹A-, and S⁺R⁹R^(10a)A-,wherein A⁻ is an pharmaceutically acceptable anion and M is apharmaceutically acceptable cation, wherein R^(10a) is selected from thegroup consisting of carboxyalkyl, carboalkoxyalkyl, carboxyalkylamino,heteroarylalkyl, and heterocyclylalkyl; or R⁶ is selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,quaternary heterocycle, OR³⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, whereinalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternaryheterocycle, and quaternary heteroaryl can be substituted with one ormore substituent groups independently selected from the group consistingof alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternaryheteroaryl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³,NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴,C(O)NR¹³R¹⁴, C(O)OM, COR¹³, NR¹³C(O)R¹⁴, NR¹³C(O)NR¹⁴R¹⁵, NR¹³CO₂R¹⁴,OC(O)R¹³, OC(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, NR¹³SONR¹⁴R¹⁵,NR¹³SO₂NR¹⁴R¹⁵, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, andN⁺R⁹R¹¹R¹²A⁻, wherein: A⁻ is a pharmaceutically acceptable anion and Mis a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl,polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle canbe further substituted with one or more substituent groups selected fromthe group consisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷,CN, oxo, CONR⁷R⁸, SR⁷, N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternaryheteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸ R⁹A⁻, and P(O)(OR⁷)OR⁸, and wherein saidalkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,cycloalkyl, and heterocycle can optionally have one or more carbonsreplaced by O, NR⁷, N⁺R⁷R⁸A⁻, S, SO, SO₂, S⁺R⁷A-, PR⁷, P(O)R⁷, P⁺R⁷R⁸A-,or phenylene, and R¹³, R¹⁴, and R¹⁵ are independently selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl,polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl,alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternaryheterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl,quaternary heterocyclylalkyl, quaternary heteroarylalkyl,alkylammoniumalkyl, and carboxyalkylaminocarbonylalkyl, wherein alkyl,alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally haveone or more carbons replaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻,PR⁹, P⁺R⁹R¹⁰A-, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, orpolypeptide, and R¹³, R¹⁴, and R¹⁵ are optionally substituted with oneor more groups selected from the group consisting of hydroxy, amino,sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl,sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternaryheterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR⁹, NR⁹R¹⁰,N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen,CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A-, S⁺R⁹R¹⁰A-, andC(O)OM, wherein R¹⁶ and R¹⁷ are independently selected from thesubstituents constituting R⁹ and M; or R¹³ and R¹⁴, together with thenitrogen atom to which they are attached form a mono- or polycyclicheterocycle that is optionally substituted with one or more radicalsselected from the group consisting of oxo, carboxy and quaternary salts;or R¹⁴ and R¹⁵, together with the nitrogen atom to which they areattached, form a cyclic ring; and R³⁰ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl,carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, andalkylammoniumalkyl; and R⁷ and R⁸ are independently selected from thegroup consisting of hydrogen and alkyl; and one or more R^(x) areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl,cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle,quaternary heteroaryl, OR¹³, NR¹³R¹⁴SR¹³, S(O)R¹³, S(O)₂R¹³, SO₃R¹³,S⁺R¹³R¹⁴A-, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂CM,SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴, NR14C(O)R13, C(O)OM, COR¹³, OR¹⁸,S(O)_(n)NR¹⁸, NR¹³R¹⁸, NR¹⁸OR¹⁴, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, amino acid,peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl,polyether, quaternary heterocycle, and quaternary heteroaryl can befurther substituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹,SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰,PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein R¹⁸ isselected from the group consisting of acyl, arylalkoxycarbonyl,arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl,arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,quaternary heterocycle, and quaternary heteroaryl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo,CO₂R⁹, CN, halogen, CONR⁹R¹⁰, 6SO₃R⁹, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷,and C(O)OM, wherein in R^(x), one or more carbons are optionallyreplaced by O, NR¹³, N⁺R¹³R¹⁴A-, S, SO, SO₂, S⁺R¹³A⁻, PR¹³, P(O)R¹³,P⁺R¹³R¹⁴A-, phenylene, amino acid, peptide, polypeptide, carbohydrate,polyether, or polyalkyl, wherein in said polyalkyl, phenylene, aminoacid, peptide, polypeptide, and carbohydrate, one or more carbons areoptionally replaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A-, PR⁹,P⁺R⁹R¹⁰A-, or P(O)R⁹; wherein quaternary heterocycle and quaternaryheteroaryl are optionally substituted with one or more groups selectedfrom the group consisting of alkyl, alkenyl, alkynyl, polyalkyl,polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen,oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴,NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴,C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵ A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, andN⁺R⁹R¹¹R¹²A⁻, or a pharmaceutically acceptable salt, solvate, or prodrugthereof.
 235. A compound of claim 234 wherein: R⁵ is phenyl substitutedwith OR^(13b); R^(13b) is alkyl; and R^(13b) is substituted withNR⁹R^(10a); and R⁹ is hydrogen; and R¹⁰ is heteroarylalkyl.
 236. Acompound of claim 234 wherein n is 1 or
 2. 237. A compound of claim 234wherein R⁷ and R⁸ are independently selected from the group consistingof hydrogen and alkyl.
 238. A compound of claim 234 wherein R⁷ and R⁸are hydrogen.
 239. A compound of claim 234 wherein R³ and R⁴ areindependently selected from the group consisting of is hydrogen and OR⁹.240. A compound of claim 234 wherein R³ is hydrogen and R⁴ is hydroxy.241. A compound of claim 234 wherein one or more R^(x) are independentlyselected from the group consisting of OR¹³ and NR¹³R¹⁴.
 242. A compoundof claim 234 wherein one or more R^(x) are independently selected frommethoxy and dimethylamino.
 243. A compound of claim 234 wherein R¹ andR² are independently selected from the group consisting of hydrogen andalkyl.
 244. A compound of claim 234 wherein R¹ and R² are independentlyselected from the group consisting alkyl.
 245. A compound of claim 234wherein R¹ and R² are the same alkyl.
 246. A compound of claim 234wherein R¹ and R² are each n-butyl.
 247. A compound of claim 234 whereinn is 1 or 2; R¹ and R² are n-butyl; R³ and R⁶ are hydrogen; R⁴ ishydroxy; R⁷ and R⁸ are hydrogen; and one or more R^(x) are independentlyselected from methoxy and dimethylamino.
 248. A compound of claim 234having the structural formula:


249. A compound of formula (I):

wherein: q is an integer from 1 to 4; n is an integer from 0 to 2; R¹and R² are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl,alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R_(w)A⁻, SR⁹, S⁺R⁹R¹⁰A⁻, P⁺R⁹R¹⁰R¹¹A⁻,S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, whereinalkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl,(polyalkyl)aryl, and cycloalkyl optionally have one or more carbonsreplaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻, P⁺R⁹R¹⁰A⁻, orphenylene, wherein R⁹, R¹⁰, and R^(w) are independently selected fromthe group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl,carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, andalkylammoniumalkyl; or R¹ and R² taken together with the carbon to whichthey are attached form C₃-C₁₀ cycloalkyl; R³ and R⁴ are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl,acyloxy, aryl, heterocycle, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹,wherein R⁹ and R¹⁰ are as defined above; or R³ and R⁴ together form ═O,═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or ═CR¹¹R¹², wherein R¹¹ and R¹² areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle,carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR⁹, NR⁹R¹⁰,SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰,wherein R⁹ and R¹⁰ are as defined above, provided that both R³ and R⁴cannot be OH, NH₂, and SH, or R¹¹ and R¹² together with the nitrogen orcarbon atom to which they are attached form a cyclic ring; R⁵ is arylsubstituted with one or more substituent groups independently selectedfrom the group consisting of NR¹³C(O)R¹⁴, NR¹³C(O)NR¹⁴R¹⁵, NR¹³C₂R¹⁴,OC(O)R¹³, OC(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, NR¹³SONR¹⁴R¹⁵, andNR¹³SO₂NR¹⁴R¹⁵, wherein: R¹³, R¹⁴, and R¹⁵ are independently selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl,polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl,alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle,heteroaryl, quaternary heterocycle, quaternary heteroaryl,heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl,quaternary heteroarylalkyl, alkylammoniumalkyl, andcarboxyalkylaminocarbonylalkyl, R¹³, R¹⁴, and R¹⁵ are optionallysubstituted with one or more groups selected from the group consistingof hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle,heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl,quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl,OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN,halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R₁₀, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A-,S⁺R⁹R¹⁰A-, and C(O)OM, wherein A⁻ is an pharmaceutically acceptableanion and M is a pharmaceutically acceptable cation, wherein R¹⁶ and R¹⁷are independently selected from the substituents constituting R⁹ and M;or R¹³ and R¹⁴, together with the nitrogen atom to which they areattached form a mono- or polycyclic heterocycle that is optionallysubstituted with one or more radicals selected from the group consistingof oxo, carboxy and quaternary salts; or R¹⁴ and R¹⁵, together with thenitrogen atom to which they are attached, form a cyclic ring; and R⁶ isselected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocycle, quaternary heterocycle, OR³⁰, SR⁹, S(O)R⁹,SO₂R⁹, and SO₃R⁹, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycle, quaternary heterocycle, and quaternary heteroaryl can besubstituted with one or more substituent groups independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, polyalkyl,polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl,quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR¹³,NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂CM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³,NR¹³C(O)R¹⁴, NR¹³C(O)NR¹⁴R¹⁵, NR¹³CO₂R¹⁴, OC(O)R¹³, OC(O)NR¹³R¹⁴,NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, NR¹³SONR¹⁴R¹⁵, NR¹³SO₂NR¹⁴R¹⁵, P(O)R¹³R¹⁴,P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R₁₂A⁻, wherein: A⁻ isa pharmaceutically acceptable anion and M is a pharmaceuticallyacceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether,aryl, haloalkyl, cycloalkyl, and heterocycle can be further substitutedwith one or more substituent groups selected from the group consistingof OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸,N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷R⁸,P⁺R⁷R⁸R⁹A⁻, and P(O)(OR⁷)OR⁸, and wherein said alkyl, alkenyl, alkynyl,polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle canoptionally have one or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A-, S, SO,SO₂, S⁺R⁷A-, PR⁷, P(O)R⁷, P⁺R⁷R⁸A-, or phenylene, and R¹³, R¹⁴, and R¹⁵are independently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl,alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle,heteroaryl, quaternary heterocycle, quaternary heteroaryl,heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl,quaternary heteroarylalkyl, alkylammoniumalkyl, andcarboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl,arylalkyl, heterocycle, and polyalkyl optionally have one or morecarbons replaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻, PR⁹,P⁺R⁹R¹⁰A-, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, orpolypeptide, and R¹³, R¹⁴, and R¹⁵ are optionally substituted with oneor more groups selected from the group consisting of hydroxy, amino,sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl,sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternaryheterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR⁹, NR⁹R¹⁰,N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen,CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶ )OR¹⁷, P⁺R⁹R¹⁰R¹¹A-, S⁺R⁹R¹⁰A-, andC(O)OM, wherein R¹⁶ and R¹⁷ are independently selected from thesubstituents constituting R⁹ and M; or R¹³ and R¹⁴, together with thenitrogen atom to which they are attached form a mono- or polycyclicheterocycle that is optionally substituted with one or more radicalsselected from the group consisting of oxo, carboxy and quaternary salts;or R¹⁴ and R¹⁵, together with the nitrogen atom to which they areattached, form a cyclic ring; and R³⁰ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl,carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, andalkylammoniumalkyl; and R⁷ and R⁸ are independently selected from thegroup consisting of hydrogen and alkyl; and one or more R^(x) areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl,cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle,quaternary heteroaryl, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, S(O)₂R¹³, SO₃R¹³,S⁺R¹³R¹⁴A-, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM,SO₂NR¹³R¹⁴, NR¹⁴C(O)¹³, C(O)NR¹³R¹⁴, NR14C(O)R13, C(O)OM, COR¹³, OR¹⁸,S(O)_(n)NR¹⁸, NR¹³R¹⁸, NR¹⁸OR¹⁴, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, amino acid,peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl,.polyether, quaternary heterocycle, and quaternary heteroaryl can befurther substituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹,SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰,PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein R¹⁸ isselected from the group consisting of acyl, arylalkoxycarbonyl,arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl,arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,quaternary heterocycle, and quaternary heteroaryl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo,CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶OR¹⁷, andC(O)OM, wherein in R^(x), one or more carbons are optionally replaced byO, NR¹³, N⁺R¹³R¹⁴A-, S, SO, SO₂, S⁺R¹³A⁻, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A-,phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, orpolyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide,polypeptide, and carbohydrate, one or more carbons are optionallyreplaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A-, PR⁹, P⁺R⁹R¹⁰A-, orP(O)R⁹; wherein quaternary heterocycle and quaternary heteroaryl areoptionally substituted with one or more groups selected from the groupconsisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³,NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂CM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³,P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻, ora pharmaceutically acceptable salt, solvate, or prodrug thereof.
 250. Acompound of claim 249 wherein R⁵ is aryl substituted with a radicalselected from the group consisting of NR¹³C(O)NR¹⁴R¹⁵ and NR¹³CO₂R¹⁴.251. A compound of claim 249 wherein R⁵ is phenyl substituted with aradical selected from the group consisting of NR¹³C(O)NR¹⁴R¹⁵ andNR¹³CO₂R¹⁴.
 252. A compound of claim 249 wherein n is 1 or
 2. 253. Acompound of claim 249 wherein R⁷ and R⁸ are independently selected fromthe group consisting of hydrogen and alkyl.
 254. A compound of claim 249wherein R⁷ and R⁸ are hydrogen.
 255. A compound of claim 249 wherein R³and R⁴ are independently selected from the group consisting of hydrogenand OR⁹.
 256. A compound of claim 249 wherein R³ is hydrogen and R⁴ ishydroxy.
 257. A compound of claim 249 wherein one or more R^(x) areindependently selected from the group consisting of OR¹³ and NR¹³R¹⁴.258. A compound of claim 249 wherein one or more R^(x) are independentlyselected from methoxy and dimethylamino.
 259. A compound of claim 249wherein R¹ and R² are independently selected from the group consistingof hydrogen and alkyl.
 260. A compound of claim 249 wherein R¹ and R²are independently selected from the group consisting alkyl.
 261. Acompound of claim 249 wherein R¹ and R² are the same alkyl.
 262. Acompound of claim 249 wherein R¹ and R² are each n-butyl.
 263. Acompound of claim 249 wherein n is 1 or 2; R¹ and R² are n-butyl; R³ andR⁶ are hydrogen; R⁴ is hydroxy; R⁷ and R⁸ are hydrogen; and one or moreR^(x) are independently selected from methoxy and dimethylamino.
 264. Acompound of claim 98 having the structural formula:


265. A pharmaceutical composition comprising an anti-hyperlipidemiccondition effective amount of a compound of formula (I) of claim 170,and a pharmaceutically acceptable carrier.
 266. A pharmaceuticalcomposition comprising an anti-atherosclerotic effective amount of acompound of formula (I) of claim 170, and a pharmaceutically acceptablecarrier.
 267. A pharmaceutical composition comprising ananti-hypercholesterolemia effective amount of a compound of formula (I)of claim 170, and a pharmaceutically acceptable carrier.
 268. A methodfor the prophylaxis or treatment of a hyperlipidemic conditioncomprising administering to a patient in need thereof a composition ofclaim 265 in unit dosage form.
 269. A method for the prophylaxis ortreatment of an atherosclerotic condition comprising administering to apatient in need thereof a composition of claim 266 in unit dosage form.270. A method for the prophylaxis or treatment of hypercholesterolemiacomprising administering to a patient in need thereof a composition ofclaim 267 in unit dosage form.
 271. A pharmaceutical compositioncomprising an anti-hyperlipidemic condition effective amount of acompound of formula (I) of claim 180, and a pharmaceutically acceptablecarrier.
 272. A pharmaceutical composition comprising ananti-atherosclerotic effective amount of a compound of formula (I) ofclaim 180, and a pharmaceutically acceptable carrier.
 273. Apharmaceutical composition comprising an anti-hypercholesterolemiaeffective amount of a compound of formula (I) of claim 180, and apharmaceutically acceptable carrier.
 274. A method for the prophylaxisor treatment of a hyperlipidemic condition comprising administering to apatient in need thereof a composition of claim 271 in unit dosage form.275. A method for the prophylaxis or treatment of an atheroscleroticcondition comprising administering to a patient in need thereof acomposition of claim 272 in unit dosage form.
 276. A method for theprophylaxis or treatment of hypercholesterolemia comprisingadministering to a patient in need thereof a composition of claim 273 inunit dosage form.
 277. A pharmaceutical composition comprising ananti-hyperlipidemic condition effective amount of a compound of formula(I) of claim 201, and a pharmaceutically acceptable carrier.
 278. Apharmaceutical composition comprising an anti-atherosclerotic effectiveamount of a compound of formula (I) of claim 201, and a pharmaceuticallyacceptable carrier.
 279. A pharmaceutical composition comprising ananti-hypercholesterolemia effective amount of a compound of formula (I)of claim 201, and a pharmaceutically acceptable carrier.
 280. A methodfor the prophylaxis or treatment of a hyperlipidemic conditioncomprising administering to a patient in need thereof a composition ofclaim 277 in unit dosage form.
 281. A method for the prophylaxis ortreatment of an atherosclerotic condition comprising administering to apatient in need thereof a composition of claim 278 in unit dosage form.282. A method for the prophylaxis or treatment of hypercholesterolemiacomprising administering to a patient in need thereof a composition ofclaim 279 in unit dosage form.
 283. A pharmaceutical compositioncomprising an anti-hyperlipidemic condition effective amount of acompound of formula (I) of claim 218, and a pharmaceutically acceptablecarrier.
 284. A pharmaceutical composition comprising ananti-atherosclerotic effective amount of a compound of formula (I) ofclaim 218, and a pharmaceutically acceptable carrier.
 285. Apharmaceutical composition comprising an anti-hypercholesterolemiaeffective amount of a compound of formula (I) of claim 218, and apharmaceutically acceptable carrier.
 286. A method for the prophylaxisor treatment of a hyperlipidemic condition comprising administering to apatient in need thereof a composition of claim 283 in unit dosage form.287. A method for the prophylaxis or treatment of an atheroscleroticcondition comprising administering to a patient in need thereof acomposition of claim 284 in unit dosage form.
 288. A method for theprophylaxis or treatment of hypercholesterolemia comprisingadministering to a patient in need thereof a composition of claim 285 inunit dosage form.
 289. A pharmaceutical composition comprising ananti-hyperlipidemic condition effective amount of a compound of formula(I) of claim 234, and a pharmaceutically acceptable carrier.
 290. Apharmaceutical composition comprising an anti-atherosclerotic effectiveamount of a compound of formula (I) of claim 234, and a pharmaceuticallyacceptable carrier.
 291. A pharmaceutical composition comprising ananti-hypercholesterolemia effective amount of a compound of formula (I)of claim 234, and a pharmaceutically acceptable carrier.
 292. A methodfor the prophylaxis or treatment of a hyperlipidemic conditioncomprising administering to a patient in need thereof a composition ofclaim 289 in unit dosage form.
 293. A method for the prophylaxis ortreatment of an atherosclerotic condition comprising administering to apatient in need thereof a composition of claim 290 in unit dosage form.294. A method for the prophylaxis or treatment of hypercholesterolemiacomprising administering to a patient in need thereof a composition ofclaim 291 in unit dosage form.
 295. A pharmaceutical compositioncomprising an anti-hyperlipidemic condition effective amount of acompound of formula (I) of claim 249, and a pharmaceutically acceptablecarrier.
 296. A pharmaceutical composition comprising ananti-atherosclerotic effective amount of a compound of formula (I) ofclaim 249, and a pharmaceutically acceptable carrier.
 297. Apharmaceutical composition comprising an anti-hypercholesterolemiaeffective amount of a compound of formula (I) of claim 249, and apharmaceutically acceptable carrier.
 298. A method for the prophylaxisor treatment of a hyperlipidemic condition comprising administering to apatient in need thereof a composition of claim 295 in unit dosage form.299. A method for the prophylaxis or treatment of an atheroscleroticcondition comprising administering to a patient in need thereof acomposition of claim 296 in unit dosage form.
 300. A method for theprophylaxis or treatment of hypercholesterolemia comprisingadministering to a patient in need thereof a composition of claim 297 inunit dosage form.
 301. A process for the preparation of a compoundhaving the formula:

comprising: treating a thiophenol with an abstracting agent; couplingthe thiophenyl and a cyclic sulfate to form an intermediate comprising asulfate group; and removing the sulfate group of the intermediate toform the compound of formula XLI; wherein q is an integer from 1 to 4;R¹ and R² are independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy,alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl,wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl,alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, andcycloalkyl optionally are substituted with one or more substituentsselected from the group consisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R^(w)A⁻, SR⁹,S⁺R⁹R¹⁰A⁻, P⁺R⁹R¹⁰R¹¹A⁻, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo,and CONR⁹R¹⁰, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy,alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or morecarbons replaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻, P⁺R⁹R¹⁰A⁻, orphenylene, wherein R⁹, R¹⁰, and R^(w) are independently selected fromthe group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl,carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, andalkylammoniumalkyl; or R¹ and R² taken together with the carbon to whichthey are attached form C₃-CIO cycloalkyl; R³ is hydroxy; R⁴ is hydrogen;R⁵ and R⁶ are independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternaryheterocycle, OR³⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle,and quaternary heteroaryl can be substituted with one or moresubstituent groups independently selected from the group consisting ofalkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternaryheteroaryl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³,NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴,C(O)NR¹³R¹⁴, C(O)OM, COR¹³, NR¹³C(O)R¹⁴, NR¹³C(O)NR¹⁴R¹⁵, NR¹³CO₂R¹⁴,OC(O)R¹³, OC(C)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, NR¹³SONR¹⁴R¹⁵,NR¹³SO₂NR¹⁴R¹⁵, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, andN⁺R⁹R¹¹R¹²A⁻, wherein: A⁻ is a pharmaceutically acceptable anion and Mis a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl,polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle canbe further substituted with one or more substituent groups selected fromthe group consisting of OR ⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷,CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl,P(O)R⁷R⁸, P⁺R⁷R⁸R⁹A⁻, and P(O)(OR⁷)OR⁸, and wherein said alkyl, alkenyl,alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, andheterocycle can optionally have one or more carbons replaced by O, NR⁷,N⁺R⁷R⁸A-, S, SO, SO₂, S⁺R⁷A-, PR⁷, P(O)R⁷, P⁺R⁷R⁸A-, or phenylene, andR¹³, R¹⁴, and R¹⁵ are independently selected from the group consistingof hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl,cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternaryheteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternaryheterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl, andcarboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl,arylalkyl, heterocycle, and polyalkyl optionally have one or morecarbons replaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻, PR⁹,P⁺R⁹R¹⁰A-, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, orpolypeptide, and R¹³, R¹⁴, and R¹⁵ are optionally substituted with oneor more groups selected from the group consisting of hydroxy, amino,sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl,sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternaryheterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR⁹, NR⁹R¹⁰,N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen,CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A-, S⁺R⁹R⁰¹A-, andC(O)OM, wherein R¹⁶ and R¹⁷ are independently selected from thesubstituents constituting R⁹ and M; or R¹³ and R¹⁴, together with thenitrogen atom to which they are attached form a mono- or polycyclicheterocycle that is optionally substituted with one or more radicalsselected from the group consisting of oxo, carboxy and quaternary salts;or R¹⁴ and R¹⁵, together with the nitrogen atom to which they areattached, form a cyclic ring; and R³⁰ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl,carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, andalkylammoniumalkyl; and R⁷ and R⁸ are hydrogen; and one or more R^(x)are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen,haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternaryheterocycle, quaternary heteroaryl, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³,S(O)₂R¹³, SO₃R¹³, S⁺R¹³R¹⁴A⁻, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN,OM, SO₂OM, SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)OM,COR¹³, OR¹⁸, S(O)_(n)NR¹⁸, NR¹³R¹⁸, NR¹⁸OR¹⁴, N⁺R⁹R¹¹R¹²A⁻,P⁺R⁹R¹¹R¹²A⁻, amino acid, peptide, polypeptide, and carbohydrate,wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl,heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternaryheterocycle, and quaternary heteroaryl can be further substituted withOR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R, SO₃R⁹, oxo, CO₂R⁹, CN,halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻,S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein R¹⁸ is selected from the groupconsisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle,heteroaryl, and alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl,heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternaryheteroaryl optionally are substituted with one or more substituentsselected from the group consisting of OR⁹, NR⁹R¹⁰, NR⁹R¹¹R¹²A⁻, SR⁹,S(O) R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM,SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, and C(O)OM, wherein in R^(x), one or morecarbons are optionally replaced by O, NR¹³ N⁺R¹³R¹⁴A⁻, S, SO, SO₂,S⁺R¹³A⁻, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A⁻, phenylene, amino acid, peptide,polypeptide, carbohydrate, polyether, or polyalkyl, wherein in saidpolyalkyl, phenylene, amino acid, peptide, polypeptide, andcarbohydrate, one or more carbons are optionally replaced by O, NR⁹,N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻, PR⁹, P⁺R⁹R¹⁰A⁻, or P(O)R⁹; whereinquaternary heterocycle and quaternary heteroaryl are optionallysubstituted with one or more groups selected from the group consistingof alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³,S(O)R¹³, SO₃R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM,SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴,P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻.
 302. Theprocess of claim 301 wherein the cyclic sulfate has the formula:

and the thiophenol has the formula:

wherein R¹, R², R⁵, R^(x) and q are as defined in claim
 301. 303. Theprocess of claim 301 wherein the sulfate group is removed by treatingthe intermediate with a hydrolyzing agent.
 304. The process of claim 303wherein the hydrolyzing agent is a mineral acid.
 305. The process ofclaim 303 wherein the hydrolyzing agent is selected from the groupconsisting of hydrochloric acid and sulfuric acid.
 306. The process ofclaim 302 wherein the abstracting agent is a base having a pH of atleast about
 10. 307. The process of claim 302 wherein the abstractingagent is an alkali metal hydride.
 308. The process of claim 302 whereinthe abstracting agent is sodium hydride.
 309. The process of claim 302wherein the R¹ and R² are alkyl.
 310. The process of claim 302 whereinthe R¹ and R² are selected from the group consisting of ethyl, n-butyl,iso-butyl and pentyl.
 311. The process of claim 302 wherein the R¹ and312.l A process for the preparation of a compound having the formula I:

comprising: reacting a cyclic sulfate with a thiophenol to form analcohol; oxidizing said alcohol to form a sulfone-aldehyde; andcyclizing said sulfone-aldehyde to form the compound of formula I;wherein: q is an integer from 1 to 4; n is 2; R¹ and R² areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl,alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R^(w)A⁻, SR⁹, S⁺R⁹R¹⁰A⁻, P⁺R⁹R¹⁰R¹A⁻,S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, whereinalkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl,(polyalkyl)aryl, and cycloalkyl optionally have one or more carbonsreplaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻, P⁺R⁹R¹⁰A⁻, orphenylene, wherein R⁹, R¹⁰, and R^(w) are independently selected fromthe group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl,carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, andalkylammoniumalkyl; or R¹ and R² taken together with the carbon to whichthey are attached form C₃-C₁₀ cycloalkyl; R³ is hydroxy; R⁴ is hydrogen;R⁵ and R⁶ are independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternaryheterocycle, OR³⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle,and quaternary heteroaryl can be substituted with one or moresubstituent groups independently selected from the group consisting ofalkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternaryheteroaryl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³,NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴,C(O)NR¹³R¹⁴, C(O)OM, COR¹³, NR¹³C(O)R¹⁴, NR¹³C(O)NR¹⁴R¹⁵, NR¹³CO₂R¹⁴,OC(O)R¹³, OC(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, NR¹³SONR¹⁴R¹⁵,NR¹³SO₂NR¹⁴R¹⁵, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, andN⁺R⁹R¹¹R¹²A⁻, wherein: A⁻ is a pharmaceutically acceptable anion and Mis a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl,polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle canbe further substituted with one or more substituent groups selected fromthe group consisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷,CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl,P(O)R⁷R⁸, P⁺R⁷R⁸R⁹A⁻, and P(C)(OR⁷)OR⁸, and wherein said alkyl, alkenyl,alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, andheterocycle can optionally have one or more carbons replaced by O, NR⁷,N⁺R⁷R⁸A-, S, SO, SO₂, S⁺R⁷A-, PR⁷, P(O)R⁷, P⁺R⁷R⁸A-, or phenylene, andR¹³, R¹⁴, and R¹⁵ are independently selected from the group consistingof hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl,cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternaryheteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternaryheterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl, andcarboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl,arylalkyl, heterocycle, and polyalkyl optionally have one or morecarbons replaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻, PR⁹,P⁺R⁹R¹⁰A-, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, orpolypeptide, and R¹³, R¹⁴, and R¹⁵ are optionally substituted with oneor more groups selected from the group consisting of hydroxy, amino,sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl,sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternaryheterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR ⁹, NR⁹R¹⁰,N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen,CONR⁹R¹⁰, SO₂OM, SO₂NR⁹, R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A-, S⁺R⁹R¹⁰A-, andC(O)OM, wherein R¹⁶ and R¹⁷ are independently selected from thesubstituents constituting R⁹ and M; or R¹³ and R¹⁴, together with thenitrogen atom to which they are attached form a mono-, or polycyclicheterocycle that is optionally substituted with one or more radicalsselected from the group consisting of oxo, carboxy and quaternary salts;or R¹⁴ and R¹⁵, together with the nitrogen atom to which they areattached, form a cyclic ring; and R³⁰ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl,carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, andalkylammoniumalkyl; and R⁷ and R⁸ are hydrogen; and one or more R^(x)are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen,haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternaryheterocycle, quaternary heteroaryl, OR³, NR¹³R¹⁴, SR¹³, S(O)R¹³,S(O)₂R¹³, SO₃R¹³, S⁺R¹³R¹⁴A⁻, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³ , CN,OM,, SO₂OM, SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(C)OM,COR¹³, OR¹⁸, S(O)_(n)NR¹⁸, NR¹³R¹⁸, NR¹⁸OR¹⁴, N⁺R⁹R¹¹R¹²A⁻,P⁺R⁹R¹¹R¹²A⁻, amino acid, peptide, polypeptide, and carbohydrate,wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl,heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternaryheterocycle, and quaternary heteroaryl can be further substituted withOR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN,halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A,S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein R¹⁸ is selected from the groupconsisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle,heteroaryl, and alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl,heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternaryheteroaryl optionally are substituted with one or more substituentsselected from the group consisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹,S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM,SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, and C(O)OM, wherein in R^(x), one or morecarbons are optionally replaced by O, NR¹³, N⁺R¹³R¹⁴A⁻, S, SO, SO₂,S⁺R¹³A⁻, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A⁻, phenylene, amino acid, peptide,polypeptide, carbohydrate, polyether, or polyalkyl, wherein in saidpolyalkyl, phenylene, amino acid, peptide, polypeptide, andcarbohydrate, one or more carbons are optionally replaced by O, NR⁹,N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻, PR⁹, P⁺R⁹R¹⁰A⁻, or P(O)R⁹; whereinquaternary heterocycle and quaternary heteroaryl are optionallysubstituted with one or more groups selected from the group consistingof alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³,S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM,SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴,P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻.
 313. Theprocess of claim 312 wherein the cyclic sulfate has the formula:

and the thiophenol has the formula:

wherein R¹, R², R⁵, R^(x) and q are as defined in claim
 312. 314. Theprocess of claim 313 wherein the R¹ and R² are alkyl.
 315. The processof claim 313 wherein the R¹ and R² are selected from the groupconsisting of ethyl, n-butyl, iso-butyl and pentyl.
 316. The process ofclaim 313 wherein the R¹ and R² are n-butyl.
 317. The process of claim313 wherein the alcohol is oxidized with an oxidizing agent to form analdehyde.
 318. The process of claim 317 wherein the aldehyde is oxidizedwith an oxidizing agent to form a sulfone-aldehyde.
 319. The process ofclaim 313 wherein the sulfone-aldehyde is cyclized with a cyclizingagent that is a base having a pH between about 8 to about
 9. 320. Theprocess of claim 313 wherein the sulfone-aldehyde is cyclized with acyclizing agent that is an alkali alkoxide base.
 321. The process ofclaim 313 wherein the sulfone-aldehyde is cyclized with potassiumtert-butoxide.
 322. The process of claim 313 wherein the alcohol isoxidized with pyridinium chlorochromate to form an aldehyde; thealdehyde is oxidized with metachloroperbenzoic acid to form asulfone-aldehyde; and the sulfone-aldehyde is cyclized with potassiumtert-butoxide.
 323. A process for the preparation of a compound havingthe formula LI:

comprising: treating a halobenzene with an abstracting agent; couplingthe halobenzene and a cyclic sulfate to form an intermediate comprisinga sulfate group; and removing the sulfate group of the intermediate toform the compound of formula LI; wherein q is an integer from 1 to 4; R¹and R² are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl,alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R^(w)A⁻, SR⁹, S⁺R⁹R¹⁰A⁻, P⁺R⁹R¹⁰R¹¹A⁻,S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, whereinalkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl,(polyalkyl)aryl, and cycloalkyl optionally have one or more carbonsreplaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻, P⁺R⁹R¹⁰A⁻, orphenylene, wherein R⁹, R10, and R^(w) are independently selected fromthe group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl,carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, andalkylammoniumalkyl; or R¹ and R² taken together with the carbon to whichthey are attached form C₃-C₁₀ cycloalkyl; R³ is hydroxy; R⁴ is hydrogen;R⁵ and R⁶ are independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternaryheterocycle, OR³⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle,and quaternary heteroaryl can be substituted with one or moresubstituent groups independently selected from the group consisting ofalkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternaryheteroaryl, halogen, oxo, OR¹³, NR¹³R¹⁴, S(O)R¹³, SO₂R¹³, SO₃R¹³,NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴,C(O)NR¹³R¹⁴, C(O)OM, COR¹³, NR¹³C(O)R¹⁴, NR¹³C(O)NR¹⁴R¹⁵, NR¹³CO₂R¹⁴,OC(O)R¹³ ₁, OC(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, NR¹³SONR¹⁴R¹⁵,NR¹³SO²NR¹⁴R¹⁵, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR³¹)OR¹⁴, S⁺R¹³R¹⁴A⁻, andN⁺R⁹R¹¹R¹²A⁻, wherein: A⁻ is a pharmaceutically acceptable anion and Mis a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl,polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle canbe further substituted with one or more substituent groups selected fromthe group consisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷,CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl,P(O)R⁷R⁸, P⁺R⁷R⁸R⁹A⁻, and P(O)(OR⁷)OR⁸, and wherein said alkyl, alkenyl,alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, andheterocycle can optionally have one or more carbons replaced by O, NR⁷,N⁺R⁷R⁸A-, S, SO, SO₂, S⁺R⁷A-, PR⁷, P(O)R⁷, P⁺R⁷R⁸A-, or phenylene, andR¹³, R¹⁴, and R¹⁵ are independently selected from the group consistingof hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl,cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternaryheteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternaryheterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl, andcarboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl,arylalkyl, heterocycle, and polyalkyl optionally have one or morecarbons replaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻, PR⁹,P⁺R⁹R¹⁰A-, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, orpolypeptide, and R¹³, R¹⁴, and R¹⁵ are optionally substituted with oneor more groups selected from the group consisting of hydroxy, amino,sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl,sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternaryheterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR ⁹, NR⁹R¹⁰,N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen,CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A-, S⁺R⁹R¹⁰A-, andC(O)OM, wherein R¹⁶ and R¹⁷ are independently selected from thesubstituents constituting R9 and M; or R¹³ and R¹⁴, together with thenitrogen atom to which they are attached form a mono- or polycyclicheterocycle that is optionally substituted with one or more radicalsselected from the group consisting of oxo, carboxy and quaternary salts;or R¹⁴ and R¹⁵, together with the nitrogen atom to which they areattached, form a cyclic ring; and R³⁰ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl,carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, andalkylammoniumalkyl; and R⁷ and R⁸ are hydrogen; and one or more R^(x)are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen,haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternaryheterocycle, quaternary heteroaryl, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³,S(O)₂R¹³, SO₃R¹³, S⁺R¹³R¹⁴A⁻, NR¹³R¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM,SO₂OM, SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)OM, COR¹³,OR¹⁸, S(O)_(n)NR¹⁸, NR¹³R¹⁸, NR¹⁸OR¹⁴, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, aminoacid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl,alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl,haloalkyl, polyether, quaternary heterocycle, and quaternary heteroarylcan be further substituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹,SO₂R, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CQNR⁹R¹⁰R, SO₂OM, SO₂NR⁹R¹⁰,PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein R¹⁸ isselected from the group consisting of acyl, arylalkoxycarbonyl,arylalkyl, heterocycle, heteroaryl, and alkyl, wherein acyl,arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,quaternary heterocycle, and quaternary heteroaryl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SC₂R⁹, SO₃R⁹, oxo,CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SC₃R⁹, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷ andC(O)OM, wherein in R^(x), one or more carbons are optionally replaced byO, NR¹³, N⁺R¹³R¹⁴A⁻, S, SO, SO₂, S⁺R¹³A⁻, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A⁻,phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, orpolyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide,polypeptide, and carbohydrate, one or more carbons are optionallyreplaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻, PR⁹, P⁺R⁹R¹⁰A⁻, orP(O)R⁹; wherein quaternary heterocycle and quaternary heteroaryl areoptionally substituted with one or more groups selected from the groupconsisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³,NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³,P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻;and R^(e) is an electron-withdrawing group located at the para or orthoposition.
 324. The process of claim 323 wherein the cyclic sulfate hasthe formula:

and the halobenzene has the formula:

wherein R^(h) is halogen, and R¹, R², R³, R^(x), R^(e) and q are asdefined in claim
 323. 325. The process of claim 324 wherein the sulfategroup is removed by treating the intermediate with a hydrolyzing agent.326. The process of claim 325 wherein the hydrolyzing agent is a mineralacid.
 327. The process of claim 325 wherein the hydrolyzing agent isselected from the group consisting of hydrochloric acid and sulfuricacid.
 328. The process of claim 324 wherein the abstracting agent is adialkali metal sulfide.
 329. The process of claim 324 wherein theabstracting agent is dilithium sulfide.
 330. The process of claim 324wherein R¹ and R² are alkyl.
 331. The process of claim 324 wherein R¹and R² are selected from the group consisting of ethyl, n-butyl,iso-butyl and pentyl.
 332. The process of claim 324 wherein R¹ and R²are n-butyl.
 333. The process of claim 324 wherein R^(h) is chloro. 334.The process of claim 324 wherein R^(e) is p-nitro.
 335. A process forthe preparation of a compound having the formula I:

comprising: reacting a cyclic sulfate with a halobenzene to form analcohol; oxidizing said alcohol to form a sulfone-aldehyde; andcyclizing said sulfone-aldehyde to form the compound of formula I;wherein q is an integer from 1 to 4; n is 2; R¹ and R² are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl,haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino,alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl,alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, NR⁹R¹⁰R^(w)A⁻, SR⁹, S⁺R⁹R¹⁰A⁻, P⁺R⁹R¹⁰R¹¹A⁻,S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, whereinalkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl,(polyalkyl)aryl, and cycloalkyl optionally have one or more carbonsreplaced by O, NR⁹, NR⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻, P⁺R⁹R¹⁰A⁻, orphenylene, wherein R⁹, R¹⁰, and R^(w) are independently selected fromthe group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl,carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, andalkylammoniumalkyl; or R¹ and R² taken together with the carbon to whichthey are attached form C₃-C₁₀ cycloalkyl; R₃ is hydroxy; R⁴ is hydrogen;R⁵ and R⁶ are independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternaryheterocycle, OR³⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle,and quaternary heteroaryl can be substituted with one or moresubstituent groups independently selected from the group consisting ofalkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternaryheteroaryl, halogen, oxo, OR⁹, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³,NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴,C(O)NR¹³R¹⁴, C(O)OM, COR¹³, NR¹³C(O)R¹⁴, NR¹³C(O)NR¹⁴R₁₅, NR¹³CO₂R¹⁴,OC(O)R¹³, OC(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, NR¹³SONR¹⁴R¹⁵,NR¹³SO₂NR¹⁴R¹⁵, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, andN⁺R⁹R¹¹R¹²A⁻, wherein: A⁻ is a pharmaceutically acceptable anion and Mis a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl,polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle canbe further substituted with one or more substituent groups selected fromthe group consisting of OR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷,CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl,P(O)R⁷R⁸, P⁺R⁷R⁸R⁹A⁻, and P(O)(OR⁷)OR⁸, and wherein said alkyl, alkenyl,alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, andheterocycle can optionally have one or more carbons replaced by O, NR⁷,N⁺R⁷R⁸A-, S, SO, SO₂, S⁺R⁷A-, PR⁷, P(O)R⁷, P⁺R⁷R⁸A-, or phenylene, andR¹³, R¹⁴, and R¹⁵ are independently selected from the group consistingof hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl,cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternaryheteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternaryheterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl, andcarboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl,arylalkyl, heterocycle, and polyalkyl optionally have one or morecarbons replaced by O, NR⁹, N⁺R⁹R¹⁰A-, S, SO, SO₂, S⁺R⁹A⁻, PR⁹,P⁺R⁹R¹⁰A-, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, orpolypeptide, and R¹³, R¹⁴, and R¹⁵ are optionally substituted with oneor more groups selected from the group consisting of hydroxy, amino,sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl,sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternaryheterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR⁹, NR⁹R¹⁰,N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen,CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A-, S⁺R⁹R¹⁰A-, andC(O)OM, wherein R¹⁶ and R¹⁷ are independently selected from thesubstituents constituting R⁹ and M; or R¹³ and R¹⁴, together with thenitrogen atom to which they are attached form a mono- or polycyclicheterocycle that is optionally substituted with one or more radicalsselected from the group consisting of oxo, carboxy and quaternary salts;or R¹⁴ and R¹⁵, together with the nitrogen atom to which they areattached, form a cyclic ring; and R³⁰ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl,carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, andalkylammoniumalkyl; and R⁷ and R⁸ are hydrogen; and one or more R^(x)are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen,haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternaryheterocycle, quaternary heteroaryl, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³,S(O)₂R¹³, SO₃R¹³, S⁺R¹³R¹⁴A⁻, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, C₂R¹³, CN, OM,SO₂OM, SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)OM, COR¹³,OR¹⁸, S(O)_(n)NR¹⁸, NR¹³R¹⁸, NR¹⁸OR¹⁴, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, aminoacid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl,alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl,haloalkyl, polyether, quaternary heterocycle, and quaternary heteroarylcan be further substituted with OR⁹, NR⁹R¹⁰, NR⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹,SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰,PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)OM, and wherein R¹⁸ isselected from the group consisting of acyl, arylalkoxycarbonyl,arylalkyl, heterocycle, heteroaryl, and alkyl, wherein acyl,arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,quaternary heterocycle, and quaternary heteroaryl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo,CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, andC(O)OM, wherein in R^(x), one or more carbons are optionally replaced byO, NR¹³, N⁺R¹³R¹⁴A⁻, S, SO, SO₂, S⁺R¹³A⁻, PR¹³, P(O)R¹³, P⁺R¹³R¹⁴A⁻,phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, orpolyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide,polypeptide, and carbohydrate, one or more carbons are optionallyreplaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻, PR⁹, P⁺R⁹R¹⁰A⁻, orP(O)R⁹; wherein quaternary heterocycle and quaternary heteroaryl areoptionally substituted with one or more groups selected from the groupconsisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³,CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴,P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻; and R^(e) isan electron-withdrawing group located at the para or ortho position.336. The process of claim 335 wherein the cyclic sulfate has theformula:

and the halobenzene has the formula:

wherein R¹, R², R⁵, R^(x) and R^(e) are as defined in claim 335, andR^(h) is halogen.
 337. The process of claim 336 wherein the sulfategroup is removed by treating the intermediate with a hydrolyzing agent.338. The process of claim 337 wherein the hydrolyzing agent is a mineralacid.
 339. The process of claim 336 wherein the hydrolyzing agent isselected from the group consisting of hydrochloric acid and sulfuricacid.
 340. The process of claim 336 wherein the abstracting agent is adialkali metal sulfide.
 341. The process of claim 336 wherein theabstracting agent is dilithium sulfide.
 342. The process of claim 336wherein R¹ and R² are alkyl.
 343. The process of claim 336 wherein R¹and R² are selected from the group consisting of ethyl, n-butyl,iso-butyl and pentyl.
 344. The process of claim 336 wherein R¹ and R²are n-butyl.
 345. The process of claim 336 wherein R^(h) is chloro. 346.The process of claim 336 wherein R^(e) is p-nitro.
 347. The process ofclaim 336 wherein the alcohol is oxidized with an oxidizing agent toform a sulfone.
 348. The process of claim 336 wherein the sulfone isoxidized with an oxidizing agent to form a sulfone-aldehyde.
 349. Theprocess of claim 336 wherein the sulfone-aldehyde is cyclized with acyclizing agent that is a base having a pH between about 8 to about 9.350. The process of claim 336 wherein the sulfone-aldehyde is cyclizedwith a cyclizing agent that is an alkali alkoxide base.
 351. The processof claim 336 wherein the sulfone-aldehyde is cyclized with potassiumtert-butoxide.
 352. The process of claim 336 wherein the alcohol isoxidized with metachloroperbenzoic acid to form a sulfone; the aldehydeis oxidized with pyridinium chlorochromate to form a sulfone-aldehyde;and the sulfone-aldehyde is cyclized with potassium tert-butoxide.